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Wang LH, Shih MY, Lin YF, Kuo PH, Feng YCA. Polygenic dissection of treatment-resistant depression with proxy phenotypes in the UK Biobank. J Affect Disord 2025; 381:350-359. [PMID: 40187433 DOI: 10.1016/j.jad.2025.04.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 03/31/2025] [Accepted: 04/01/2025] [Indexed: 04/07/2025]
Abstract
BACKGROUND Treatment-resistant depression (TRD) affects one-third of major depressive disorder (MDD) patients. Previous pharmacogenetic studies suggest genetic variation may influence medication response but findings are heterogeneous. We conducted a comprehensive genetic investigation using proxy TRD phenotypes (TRDp) that mirror the treatment options of MDD from UK Biobank primary care records. METHODS Among 15,125 White British MDD patients, we identified TRDp with medication changes (switching or receiving multiple antidepressants [AD]); augmentation therapy (antipsychotics; mood stabilizers; valproate; lithium); or electroconvulsive therapy (ECT). Hospitalized TRDp patients (HOSP-TRDp) were also identified. We conducted genome-wide association analysis, estimated SNP-heritability (hg2), and assessed the genetic burden for nine psychiatric diseases using polygenic risk scores (PRS). RESULTS TRDp patients were more often female, unemployed, less educated, and had higher BMI, with hospitalization rates twice as high as non-TRDp. While no credible risk variants emerged, heritability analysis showed significant genetic influence on TRDp (liability hg2 21-24 %), particularly for HOSP-TRDp (28-31 %). TRDp classified by AD changes and augmentation carried an elevated yet varied polygenic burden for MDD, ADHD, BD, and SCZ. Higher BD PRS increased the likelihood of receiving ECT, lithium, and valproate by 1.27-1.80 fold. Patients in the top 10 % PRS relative to the average had a 12-36 % and 24-51 % higher risk of TRDp and HOSP-TRDp, respectively. CONCLUSIONS Our findings support a significant polygenic basis for TRD, highlighting genetic and phenotypic distinctions from non-TRD. We demonstrate that different TRDp endpoints are enriched with various spectra of psychiatric genetic liability, offering insights into pharmacogenomics and TRD's complex genetic architecture.
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Affiliation(s)
- Ling-Hua Wang
- Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University, Taiwan
| | - Mu-Yi Shih
- Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University, Taiwan; Department of Public Health, College of Public Health, National Taiwan University, Taiwan
| | - Yen-Feng Lin
- Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan; Department of Public Health & Medical Humanities, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Po-Hsiu Kuo
- Department of Public Health, College of Public Health, National Taiwan University, Taiwan; Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Chen A Feng
- Institute of Health Data Analytics and Statistics, College of Public Health, National Taiwan University, Taiwan; Department of Public Health, College of Public Health, National Taiwan University, Taiwan; Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
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Rezende RC, He W, Kaisinger LR, Lerario AM, Schafer EC, Kentistou KA, Barroso PS, Andrade NLM, Dantas NCB, Costa EMF, Cellin LP, P S Quedas E, Seminara SB, Rey RA, Grinspon RP, Meriq V, Ong KK, Latronico AC, Perry JRB, Howard SR, Chan YM, Jorge AAL. Deleterious variants in intolerant genes reveal new candidates for self-limited delayed puberty. Eur J Endocrinol 2025; 192:481-490. [PMID: 40193575 PMCID: PMC12013340 DOI: 10.1093/ejendo/lvaf061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 03/27/2025] [Accepted: 04/03/2025] [Indexed: 04/09/2025]
Abstract
OBJECTIVE Self-limited delayed puberty (SLDP) is the most common cause of delayed puberty and exhibits high heritability, although few causal genes have been identified. This study aims to identify potential candidate genes associated with SLDP. METHODS Whole-exome sequencing was conducted in 71 children with SLDP, most of whom presented with short stature. Rare coding variants were prioritized through comprehensive bioinformatics analyses and classified as high-impact or moderate-impact based on predicted functional effects. Candidate genes were selected based on the absence of human phenotype data, recurrence within the cohort, intolerance to mutation, and prior identification in genome-wide association studies. Burden tests compared the frequency of rare high-impact variants in these candidate genes between SLDP patients and the gnomAD v2.0 control group. Gene-phenotype associations were further explored using UK Biobank data. RESULTS Fourteen high-impact and 7 moderate-impact variants were identified in 19 candidate genes, suggesting a potential role in SLDP. Variants in 8 candidate genes (GPS1, INHBB, SP3, NAMPT, ARID3B, NASP, FNBP1, PRDM2) were significantly enriched in cases compared to controls in the burden test analysis. INHBB was additionally linked to delayed menarche in UK Biobank data. Furthermore, 3 pathogenic variants (CDK13, GDF5, ANRKD11) and 6 likely pathogenic variants (TYMP, DPF2, KMT2C, TP63, MC3R, GHSR) previously associated with growth or pubertal human disorders were identified. CONCLUSION These findings suggest that SLDP involves both monogenic and polygenic mechanisms, with novel candidate genes contributing to its genetic basis. The association of INHBB with pubertal timing underscores its potential role in SLDP pathophysiology.
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Affiliation(s)
- Raíssa C Rezende
- Unidade de Endocrinologia Genetica (LIM 25), Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, SP 0124690, Brazil
| | - Wen He
- Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, United States
| | - Lena R Kaisinger
- MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom
| | - Antonio M Lerario
- Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, United States
| | - Evan C Schafer
- Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, United States
| | - Katherine A Kentistou
- MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom
| | - Priscila S Barroso
- Unidade de Endocrinologia Genetica (LIM 25), Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, SP 0124690, Brazil
| | - Nathalia L M Andrade
- Unidade de Endocrinologia Genetica (LIM 25), Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, SP 0124690, Brazil
| | - Naiara C B Dantas
- Unidade de Endocrinologia Genetica (LIM 25), Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, SP 0124690, Brazil
| | - Elaine Maria F Costa
- Unidade de Endocrinologia Genetica (LIM 25), Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, SP 0124690, Brazil
| | - Laurana P Cellin
- Unidade de Endocrinologia Genetica (LIM 25), Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, SP 0124690, Brazil
| | - Elisangela P S Quedas
- Unidade de Endocrinologia Genetica (LIM 25), Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, SP 0124690, Brazil
| | - Stephanie B Seminara
- Massachusetts General Hospital Harvard Center for Reproductive Medicine and Reproductive Endocrine Unit, Massachusetts General Hospital, Bartlett Hall Extension, 5th Floor, 55 Fruit Street, Boston, MA 02114, United States
| | - Rodolfo A Rey
- Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE), CONICET–FEI–Divisièn de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330, C1425EFD Buenos Aires, Argentina
| | - Romina P Grinspon
- Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE), CONICET–FEI–Divisièn de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330, C1425EFD Buenos Aires, Argentina
| | - Veronica Meriq
- Institute of Maternal and Child Research, Faculty of Medicine, University of Chile, Santa Rosa 1234, 2° piso, Santiago 8320000, Chile
| | - Ken K Ong
- MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom
| | - Ana Claudia Latronico
- Unidade de Endocrinologia Genetica (LIM 25), Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, SP 0124690, Brazil
| | - John R B Perry
- MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom
- Metabolic Research Laboratory, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge CB2 0QQ, United Kingdom
| | - Sasha R Howard
- Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom
| | - Yee-Ming Chan
- Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, United States
- Department of Pediatrics, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, United States
| | - Alexander A L Jorge
- Unidade de Endocrinologia Genetica (LIM 25), Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, SP 0124690, Brazil
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Yu S, Wang C, Ouyang J, Luo T, Zeng F, Zhang Y, Gao L, Huang S, Wang X. Identification of candidate biomarkers correlated with the pathogenesis of breast cancer patients. Sci Rep 2025; 15:8770. [PMID: 40082607 PMCID: PMC11906855 DOI: 10.1038/s41598-025-93208-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 03/05/2025] [Indexed: 03/16/2025] Open
Abstract
Breast cancer (BC) is the second leading cause of cancer-related death in females, followed by lung cancer. Disadvantages exist in conventional diagnostic techniques of BC, such as radiation risk. The present study integrated bioinformatics analysis with machine learning to elucidate potential key candidate genes associated with the tumorigenesis of BC. Eleven datasets were downloaded from the Gene Expression Omnibus (GEO) database and were consolidated into two independent cohorts (training cohort and validation cohort) after batch-effect removal. We employed "limma" package to screen differentially expressed genes (DEGs) between BC and adjacent normal breast samples. Subsequently, the most reliable diagnostic indicators were identified utilizing LASSO-Logistic regression, SVM-RFE and multivariate stepwise Logistic regression analysis. Logistic model and nomogram were created based on these hub genes and applied in external validation cohort to verify the robustness of the model. As a result, a total of six hub genes connected with BC pathogenesis were identified, including CD300LG, IGSF10, FAM83D, MAMDC2, COMP and SEMA3G. Then, a diagnostic model of BC on the basis of these genes was established. ROC analysis of the diagnostic model illustrated that AUC of the training cohort was 0.978 (0.962, 0.995). In the validation cohort, AUC of training set and validation set were 0.936 (0.910, 0.961) and 0.921 (0.870, 0.972), respectively. This indicated that the model was reliable in separating BC patients from healthy individuals. The model may assist in early diagnosis of BC with implications for improving the prognosis of BC patients.
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Affiliation(s)
- Shiqun Yu
- Yunfu Center for Disease Control and Prevention, Yunfu, China
- Jiangxi Provincial Key Laboratory of Cell Precision Therapy, School of Basic Medical Sciences , Jiujiang University, Jiujiang, 332005, Jiangxi, China
| | - Chengman Wang
- School of Public Health, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
- Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health, Nanchang University, Nanchang, 330006, China
| | - Jin Ouyang
- Jiangxi Key Laboratory of Molecular Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Jiangxi Provincial Key Laboratory of Cell Precision Therapy, School of Basic Medical Sciences , Jiujiang University, Jiujiang, 332005, Jiangxi, China
| | - Ting Luo
- Infection Control Center, The First Affiliated Hospital of Nanchang University, Nanchang, 330000, China
- Jiangxi Provincial Key Laboratory of Cell Precision Therapy, School of Basic Medical Sciences , Jiujiang University, Jiujiang, 332005, Jiangxi, China
| | - Fanfan Zeng
- School of Public Health, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
- Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health, Nanchang University, Nanchang, 330006, China
| | - Yu Zhang
- School of Public Health, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China
- Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health, Nanchang University, Nanchang, 330006, China
| | - Liyun Gao
- Jiangxi Provincial Key Laboratory of Cell Precision Therapy, School of Basic Medical Sciences , Jiujiang University, Jiujiang, 332005, Jiangxi, China
| | - Shaoxin Huang
- Jiangxi Provincial Key Laboratory of Cell Precision Therapy, School of Basic Medical Sciences , Jiujiang University, Jiujiang, 332005, Jiangxi, China
| | - Xin Wang
- Jiangxi Provincial Key Laboratory of Cell Precision Therapy, School of Basic Medical Sciences , Jiujiang University, Jiujiang, 332005, Jiangxi, China.
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Fanis P, Morrou M, Tomazou M, Alghol HAM, Spyrou GM, Neocleous V, Phylactou LA. Identification of puberty related miRNAs in the hypothalamus of female mice. Mol Cell Endocrinol 2025; 598:112468. [PMID: 39842623 DOI: 10.1016/j.mce.2025.112468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 01/03/2025] [Accepted: 01/20/2025] [Indexed: 01/24/2025]
Abstract
BACKGROUND AND AIMS Puberty is a crucial developmental stage marked by the transition from childhood to adulthood, organized by complex hormonal signaling within the neuroendocrine system. The hypothalamus, a central region in this system, regulates pubertal functions through the hypothalamic-pituitary-gonadal (HPG) axis. Gonadotropin-releasing hormone (GnRH) neurons, essential in puberty control, release GnRH in a pulsatile manner, initiating the production of sex hormones. Major influence in pubertal timing has been attributed to genetic predisposition, environmental factors, and nutritional status. MicroRNAs (miRNAs), small non-coding RNA molecules, have emerged as key regulators in various cellular processes by either repressing genes or activating them by inhibiting their repressors. The present study aims to investigate the involvement of miRNAs in the control of puberty. METHODS Small RNA sequencing was used to identify and compare the total population of miRNAs in the hypothalamus of female mice before, during and after puberty. Bioinformatic analysis was applied to analyse the expression profile of miRNAs with altered levels followed by pathway enrichment analysis. RESULTS Expression levels of several miRNAs were found up- or down-regulated from pre-pubertal to pubertal stage. Furthermore, monitoring the levels of these miRNAs at the post-pubertal stage revealed four expression patterns, in which pathway analysis displayed the associations of these miRNAs with developmental processes, cell cycle regulation, metabolic biosynthesis and epigenetic regulation. CONCLUSION The findings of the present study improve our understanding of the molecular pathways underlying puberty and stress the significance of miRNAs in fine-tuning gene expression within the hypothalamus during this critical developmental stage.
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Affiliation(s)
- Pavlos Fanis
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Maria Morrou
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Marios Tomazou
- Department of Bioinformatics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Hend Abdulgadr M Alghol
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - George M Spyrou
- Department of Bioinformatics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Vassos Neocleous
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Leonidas A Phylactou
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
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Lippincott MF, Schafer EC, Hindman AA, He W, Brauner R, Delaney A, Grinspon R, Hall JE, Hirschhorn JN, McElreavey K, Palmert MR, Rey R, Seminara SB, Salem RM, Chan YM. Contributions of Common Genetic Variants to Constitutional Delay of Puberty and Idiopathic Hypogonadotropic Hypogonadism. J Clin Endocrinol Metab 2024; 110:e61-e67. [PMID: 38477512 PMCID: PMC11651688 DOI: 10.1210/clinem/dgae166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 03/09/2024] [Accepted: 03/11/2024] [Indexed: 03/14/2024]
Abstract
CONTEXT Constitutional delay of puberty (CDP) is highly heritable, but the genetic basis for CDP is largely unknown. Idiopathic hypogonadotropic hypogonadism (IHH) can be caused by rare genetic variants, but in about half of cases, no rare-variant cause is found. OBJECTIVE To determine whether common genetic variants that influence pubertal timing contribute to CDP and IHH. DESIGN Case-control study. PARTICIPANTS 80 individuals with CDP; 301 with normosmic IHH, and 348 with Kallmann syndrome (KS); control genotyping data from unrelated studies. MAIN OUTCOME MEASURES Polygenic scores (PGS) based on genome-wide association studies for timing of male pubertal hallmarks and age at menarche (AAM). RESULTS The CDP cohort had higher PGS for male pubertal hallmarks and for AAM compared to controls (for male hallmarks, Cohen's d = 0.67, P = 1 × 10-10; for AAM, d = 0.85, P = 1 × 10-16). The normosmic IHH cohort also had higher PGS for male hallmarks compared to controls, but the difference was smaller (male hallmarks d = 0.20, P = .003; AAM d = 0.10, P = .055). No differences were seen for the KS cohort compared to controls (male hallmarks d = 0.05, P = .45; AAM d = 0.03, P = .56). CONCLUSION Common genetic variants that influence pubertal timing in the general population contribute strongly to the genetics of CDP, weakly to normosmic IHH, and potentially not at all to KS. These findings demonstrate that the common-variant genetics of CDP and normosmic IHH are largely but not entirely distinct.
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Affiliation(s)
- Margaret F Lippincott
- Harvard Center for Reproductive Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Departments of Medicine (M.F.L., S.B.S.), Pediatrics (J.N.H., Y.-M.C.), and Genetics (J.N.H.), Harvard Medical School, Boston, MA 02115, USA
| | - Evan C Schafer
- Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA
| | - Anna A Hindman
- Harvard Center for Reproductive Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Wen He
- Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA
| | - Raja Brauner
- Unité d'Endocrinologie Pédiatrique et Troubles de la Croissance, Hôpital Fondation Adolphe de Rothschild and Université Paris Cité, 75019 Paris, France
| | - Angela Delaney
- Division of Endocrinology, Department of Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Romina Grinspon
- Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE), CONICET—FEI—División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, C1425EFD, Buenos Aires, Argentina
| | - Janet E Hall
- Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Durham, NC 27709, USA
| | - Joel N Hirschhorn
- Departments of Medicine (M.F.L., S.B.S.), Pediatrics (J.N.H., Y.-M.C.), and Genetics (J.N.H.), Harvard Medical School, Boston, MA 02115, USA
- Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA
- Programs in Medical and Population Genetics (J.N.H., S.B.S., Y.-M.C.) and Metabolism (J.N.H.), Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Kenneth McElreavey
- Human Developmental Genetics, CNRS UMR3738, Institut Pasteur, 75015 Paris, France
| | - Mark R Palmert
- Division of Endocrinology, Hospital for Sick Children, Departments of Pediatrics and Physiology, University of Toronto, Toronto, ON M5G 1E8, Canada
| | - Rodolfo Rey
- Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE), CONICET—FEI—División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, C1425EFD, Buenos Aires, Argentina
| | - Stephanie B Seminara
- Harvard Center for Reproductive Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Departments of Medicine (M.F.L., S.B.S.), Pediatrics (J.N.H., Y.-M.C.), and Genetics (J.N.H.), Harvard Medical School, Boston, MA 02115, USA
- Programs in Medical and Population Genetics (J.N.H., S.B.S., Y.-M.C.) and Metabolism (J.N.H.), Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Rany M Salem
- Herbert Wertheim School of Public Health & Human Longevity Science, University of San Diego, La Jolla, CA 92093, USA
| | - Yee-Ming Chan
- Departments of Medicine (M.F.L., S.B.S.), Pediatrics (J.N.H., Y.-M.C.), and Genetics (J.N.H.), Harvard Medical School, Boston, MA 02115, USA
- Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA
- Programs in Medical and Population Genetics (J.N.H., S.B.S., Y.-M.C.) and Metabolism (J.N.H.), Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
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Read JE, Vasile‐Tudorache A, Newsome A, Lorente MJ, Agustín‐Pavón C, Howard SR. Disorders of puberty and neurodevelopment: A shared etiology? Ann N Y Acad Sci 2024; 1541:83-99. [PMID: 39431640 PMCID: PMC11580780 DOI: 10.1111/nyas.15246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2024]
Abstract
The neuroendocrine control of puberty and reproduction is fascinatingly complex, with up- and down-regulation of key reproductive hormones during fetal, infantile, and later childhood periods that determine the correct function of the hypothalamic-pituitary-gonadal axis and the timing of puberty. Neuronal development is a vital element of these processes, and multiple conditions of disordered puberty and reproduction have their etiology in abnormal neuronal migration or function. Although there are numerous documented cases across multiple conditions wherein patients have both neurodevelopmental disorders and pubertal abnormalities, this has mostly been described ad hoc and the associations are not clearly documented. In this review, we aim to describe the overlap between these two groups of conditions and to increase awareness to ensure that puberty and reproductive function are carefully monitored in patients with neurodevelopmental conditions, and vice versa. Moreover, this commonality can be explored for clues about the disease mechanisms in these patient groups and provide new avenues for therapeutic interventions for affected individuals.
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Affiliation(s)
- Jordan E. Read
- Centre for Endocrinology, William Harvey Research InstituteQueen Mary University of LondonLondonUK
| | - Alexandru Vasile‐Tudorache
- Department of Cell Biology, Functional Biology and Physical AnthropologyFaculty of Biological Sciences, University of ValenciaValenciaSpain
| | - Angel Newsome
- Centre for Endocrinology, William Harvey Research InstituteQueen Mary University of LondonLondonUK
| | - María José Lorente
- Department of Cell Biology, Functional Biology and Physical AnthropologyFaculty of Biological Sciences, University of ValenciaValenciaSpain
| | - Carmen Agustín‐Pavón
- Department of Cell Biology, Functional Biology and Physical AnthropologyFaculty of Biological Sciences, University of ValenciaValenciaSpain
| | - Sasha R. Howard
- Centre for Endocrinology, William Harvey Research InstituteQueen Mary University of LondonLondonUK
- Department of Paediatric EndocrinologyBarts Health NHS TrustLondonUK
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Yang X, Wang Z, Chen Y, Ding H, Fang Y, Ma X, Liu H, Guo J, Zhao J, Wang J, Lu W. ALKBH5 Reduces BMP15 mRNA Stability and Regulates Bovine Puberty Initiation Through an m6A-Dependent Pathway. Int J Mol Sci 2024; 25:11605. [PMID: 39519156 PMCID: PMC11546126 DOI: 10.3390/ijms252111605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 10/25/2024] [Accepted: 10/27/2024] [Indexed: 11/16/2024] Open
Abstract
The timing of puberty significantly influences subsequent reproductive performance in cattle. N6-methyladenosine (m6A) is a key epigenetic modification involved in the regulation of pubertal onset. However, limited research has investigated alterations in m6A methylation within the hypothalamic-pituitary-ovarian (HPO) axis during the onset of puberty. In this study, combined analysis of methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and RNA sequencing (RNA-seq) is used to describe the overall modification pattern of m6A in the HPO axis, while GSEA, KEGG, and GO analyses are used to describe the enrichment pathways of differentially expressed genes and differentially methylated genes. The m6A modifications of the differential genes KL, IGSF10, PAPPA2, and BMP15 and the pathways of cell adhesion molecules (CAMs), TGF-β, cell cycle, and steroid hormone synthesis may play roles in regulating the function of the HPO axis tissue during pubertal transition. Notably, BMP15's m6A modification depends on the action of the demethylase ALKBH5, which is recognized by the reader protein YTHDF2, promoting bovine granulosa cell proliferation, steroid production, and estrogen secretion. This study reveals for the first time the modification mechanism of BMP15 m6A during the initiation of bovine puberty, which will provide useful information for improving the reproductive efficiency of Chinese beef cattle.
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Affiliation(s)
- Xiaorui Yang
- Key Laboratory of Animal Production, Product Quality and Security, Ministry of Education, Jilin Agricultural University, Changchun 130118, China; (X.Y.); (Z.W.); (Y.C.); (H.D.); (Y.F.); (X.M.); (H.L.); (J.G.); (J.Z.)
- Jilin Province Engineering Laboratory for Ruminant Reproductive Biotechnology and Healthy Production, College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China
| | - Ziming Wang
- Key Laboratory of Animal Production, Product Quality and Security, Ministry of Education, Jilin Agricultural University, Changchun 130118, China; (X.Y.); (Z.W.); (Y.C.); (H.D.); (Y.F.); (X.M.); (H.L.); (J.G.); (J.Z.)
- Jilin Province Engineering Laboratory for Ruminant Reproductive Biotechnology and Healthy Production, College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China
| | - Yue Chen
- Key Laboratory of Animal Production, Product Quality and Security, Ministry of Education, Jilin Agricultural University, Changchun 130118, China; (X.Y.); (Z.W.); (Y.C.); (H.D.); (Y.F.); (X.M.); (H.L.); (J.G.); (J.Z.)
- Jilin Province Engineering Laboratory for Ruminant Reproductive Biotechnology and Healthy Production, College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China
| | - He Ding
- Key Laboratory of Animal Production, Product Quality and Security, Ministry of Education, Jilin Agricultural University, Changchun 130118, China; (X.Y.); (Z.W.); (Y.C.); (H.D.); (Y.F.); (X.M.); (H.L.); (J.G.); (J.Z.)
- Jilin Province Engineering Laboratory for Ruminant Reproductive Biotechnology and Healthy Production, College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China
| | - Yi Fang
- Key Laboratory of Animal Production, Product Quality and Security, Ministry of Education, Jilin Agricultural University, Changchun 130118, China; (X.Y.); (Z.W.); (Y.C.); (H.D.); (Y.F.); (X.M.); (H.L.); (J.G.); (J.Z.)
- Jilin Province Engineering Laboratory for Ruminant Reproductive Biotechnology and Healthy Production, College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China
| | - Xin Ma
- Key Laboratory of Animal Production, Product Quality and Security, Ministry of Education, Jilin Agricultural University, Changchun 130118, China; (X.Y.); (Z.W.); (Y.C.); (H.D.); (Y.F.); (X.M.); (H.L.); (J.G.); (J.Z.)
- Jilin Province Engineering Laboratory for Ruminant Reproductive Biotechnology and Healthy Production, College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China
| | - Hongyu Liu
- Key Laboratory of Animal Production, Product Quality and Security, Ministry of Education, Jilin Agricultural University, Changchun 130118, China; (X.Y.); (Z.W.); (Y.C.); (H.D.); (Y.F.); (X.M.); (H.L.); (J.G.); (J.Z.)
- Jilin Province Engineering Laboratory for Ruminant Reproductive Biotechnology and Healthy Production, College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China
| | - Jing Guo
- Key Laboratory of Animal Production, Product Quality and Security, Ministry of Education, Jilin Agricultural University, Changchun 130118, China; (X.Y.); (Z.W.); (Y.C.); (H.D.); (Y.F.); (X.M.); (H.L.); (J.G.); (J.Z.)
- Jilin Province Engineering Laboratory for Ruminant Reproductive Biotechnology and Healthy Production, College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China
| | - Jing Zhao
- Key Laboratory of Animal Production, Product Quality and Security, Ministry of Education, Jilin Agricultural University, Changchun 130118, China; (X.Y.); (Z.W.); (Y.C.); (H.D.); (Y.F.); (X.M.); (H.L.); (J.G.); (J.Z.)
- Jilin Province Engineering Laboratory for Ruminant Reproductive Biotechnology and Healthy Production, College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China
| | - Jun Wang
- Key Laboratory of Animal Production, Product Quality and Security, Ministry of Education, Jilin Agricultural University, Changchun 130118, China; (X.Y.); (Z.W.); (Y.C.); (H.D.); (Y.F.); (X.M.); (H.L.); (J.G.); (J.Z.)
- Jilin Province Engineering Laboratory for Ruminant Reproductive Biotechnology and Healthy Production, College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China
| | - Wenfa Lu
- Key Laboratory of Animal Production, Product Quality and Security, Ministry of Education, Jilin Agricultural University, Changchun 130118, China; (X.Y.); (Z.W.); (Y.C.); (H.D.); (Y.F.); (X.M.); (H.L.); (J.G.); (J.Z.)
- Jilin Province Engineering Laboratory for Ruminant Reproductive Biotechnology and Healthy Production, College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China
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8
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Damon J, Chase C, Higashimoto T. Primary amenorrhea in myotonic dystrophy type 1: Initial presentation versus incidental finding on whole genome sequencing. Am J Med Genet A 2024; 194:e63650. [PMID: 38709060 DOI: 10.1002/ajmg.a.63650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 04/18/2024] [Accepted: 04/24/2024] [Indexed: 05/07/2024]
Abstract
Myotonic dystrophy type 1 is an autosomal dominant condition due to a CTG repeat expansion in the myotonic dystrophy protein kinase (DMPK) gene. This multisystem disorder affects multiple organ systems. Hypogonadism in males affected by myotonic dystrophy is commonly reported; however, the effect on female hypogonadism remains controversial. A 19-year-old female was referred to our genetics clinic due to primary amenorrhea without any family history of similar symptoms. Initial genetics evaluation identified a variant of uncertain significance in IGSF10, c.2210T>C (p.Phe737Ser). Follow-up genetic evaluation via whole genome sequencing identified at least 100 CTG repeats in the DMPK gene, thus resulting in the diagnosis of myotonic dystrophy type 1. The patient remains otherwise asymptomatic from myotonic dystrophy. This is the first report that demonstrates primary amenorrhea as a possible presenting feature of myotonic dystrophy type 1, thus providing evidence supporting female hypogonadism in myotonic dystrophy type 1.
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Affiliation(s)
- Jenna Damon
- Department of Internal Medicine, Division of Genetic Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Colby Chase
- Department of Internal Medicine, Division of Genetic Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Tomoyasu Higashimoto
- Department of Internal Medicine, Division of Genetic Medicine, University of Michigan, Ann Arbor, Michigan, USA
- Department of Pediatrics, Division of Genetics, Genomics, and Metabolism, University of Michigan, Ann Arbor, Michigan, USA
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9
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Harrington J. Delayed Puberty Including Constitutional Delay: Differential and Outcome. Endocrinol Metab Clin North Am 2024; 53:267-278. [PMID: 38677869 DOI: 10.1016/j.ecl.2024.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2024]
Abstract
Constitutional delay of growth and puberty (CDGP) is the most common cause of delayed puberty in both male and female individuals. This article reviews the causes of delayed puberty focusing on CDGP, including new advances in the understanding of the genetics underpinning CDGP, a clinical approach to discriminating CDGP from other causes of delayed puberty, outcomes, as well as current and potential emerging management options.
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Affiliation(s)
- Jennifer Harrington
- Division of Endocrinology, Women's and Children's Health Network, Adelaide, Australia; Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia.
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10
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Neocleous V, Fanis P, Toumba M, Skordis N, Phylactou LA. Genetic diagnosis of endocrine disorders in Cyprus through the Cyprus Institute of Neurology and Genetics: an ENDO-ERN Reference Center. Orphanet J Rare Dis 2024; 19:167. [PMID: 38637882 PMCID: PMC11027394 DOI: 10.1186/s13023-024-03171-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 03/30/2024] [Indexed: 04/20/2024] Open
Abstract
The report covers the current and past activities of the department Molecular Genetics-Function and Therapy (MGFT) at the Cyprus Institute of Neurology and Genetics (CING), an affiliated Reference Center for the European Reference Network on Rare Endocrine Conditions (Endo-ERN).The presented data is the outcome of > 15 years long standing collaboration between MGFT and endocrine specialists from the local government hospitals and the private sector. Up-to-date > 2000 genetic tests have been performed for the diagnosis of inherited rare endocrine disorders. The major clinical entities included Congenital Adrenal Hyperplasia (CAH) due to pathogenic variants in CYP21A2 gene and Multiple Endocrine Neoplasia (MEN) type 2 due to pathogenic variants in the RET proto-oncogene. Other rare and novel pathogenic variants in ANOS1, WDR11, FGFR1, RNF216, and CHD7 genes were also found in patients with Congenital Hypogonadotropic Hypogonadism. Interestingly, a few patients with Disorders of Sexual Differentiation (DSD) shared rare pathogenic variants in the SRD5A2, HSD17B3 and HSD3B2 while patients with Glucose and Insulin Homeostasis carried theirs in GCK and HNF1A genes. Lastly, MGFT over the last few years has established an esteemed diagnostic and research program on premature puberty with emphasis on the implication of MKRN3 gene on the onset of the disease and the identification of other prognosis biomarkers.As an Endo-ERN member MGFT department belongs to this large European network and holds the same humanistic ideals which aim toward the improvements of health care for patients with rare endocrine conditions in respect to improved and faster diagnosis.
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Affiliation(s)
- Vassos Neocleous
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Pavlos Fanis
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - Meropi Toumba
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
- Department of Pediatrics, Pediatric Endocrinology Clinic, Aretaeio Hospital, Nicosia, Cyprus
| | - Nicos Skordis
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
- Division of Paediatric Endocrinology, Paedi Center for Specialized Paediatrics, Nicosia, Cyprus
- School of Medicine, University of Nicosia, Nicosia, Cyprus
| | - Leonidas A Phylactou
- Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
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11
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Ling B, Ye G, Qin C, Liao X, Yang R, Su L, Qi G. IGSF10 inhibits the metastasis of lung adenocarcinoma via the Spi-B/Integrin-β1 signaling pathway. J Biochem Mol Toxicol 2024; 38:e23693. [PMID: 38622980 DOI: 10.1002/jbt.23693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 06/16/2023] [Accepted: 03/12/2024] [Indexed: 04/17/2024]
Abstract
IGSF10, a protein that belongs to the immunoglobulin superfamily, is involved in regulating the early migration of neurons that produce gonadotropin-releasing hormone and performs a fundamental function in development. Our previous study confirmed that the mRNA expression level of IGSF10 may be a protective prognosis factor for lung adenocarcinoma (LUAD) patients. However, the specific mechanisms of IGSF10 are still unclear. In this research, it was shown that the protein level of IGSF10 was down-modulated in LUAD tissues and had a link to the clinical and pathological characteristics as well as the patient's prognosis in LUAD. Importantly, IGSF10 regulates the metastatic ability of LUAD cells in vitro and in vivo. It was proven in a mechanistic sense that IGSF10 inhibits the capacity of LUAD cells to metastasize through the Spi-B/Integrin-β1 signaling pathway. These findings gave credence to the premise that IGSF10 performed a crucial function in LUAD.
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Affiliation(s)
- Bo Ling
- College of Pharmacy, Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Guangbin Ye
- College of basic Medical Sciences, Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Chunyan Qin
- Department of Pulmonary and Critical Care Medicine, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Xianjiu Liao
- College of Pharmacy, Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Ruirui Yang
- Institute of Life Sciences, Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Lili Su
- Institute of Life Sciences, Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Guangzi Qi
- College of public health and management, Youjiang Medical University for Nationalities, Baise, Guangxi, China
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12
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Akinyemi RO, Tiwari HK, Srinivasasainagendra V, Akpa O, Sarfo FS, Akpalu A, Wahab K, Obiako R, Komolafe M, Owolabi L, Osaigbovo GO, Mamaeva OA, Halloran BA, Akinyemi J, Lackland D, Obiabo OY, Sunmonu T, Chukwuonye II, Arulogun O, Jenkins C, Adeoye A, Agunloye A, Ogah OS, Ogbole G, Fakunle A, Uvere E, Coker MM, Okekunle A, Asowata O, Diala S, Ogunronbi M, Adeleye O, Laryea R, Tagge R, Adeniyi S, Adusei N, Oguike W, Olowoyo P, Adebajo O, Olalere A, Oladele O, Yaria J, Fawale B, Ibinaye P, Oyinloye O, Mensah Y, Oladimeji O, Akpalu J, Calys-Tagoe B, Dambatta HA, Ogunniyi A, Kalaria R, Arnett D, Rotimi C, Ovbiagele B, Owolabi MO. Novel functional insights into ischemic stroke biology provided by the first genome-wide association study of stroke in indigenous Africans. Genome Med 2024; 16:25. [PMID: 38317187 PMCID: PMC10840175 DOI: 10.1186/s13073-023-01273-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 12/12/2023] [Indexed: 02/07/2024] Open
Abstract
BACKGROUND African ancestry populations have the highest burden of stroke worldwide, yet the genetic basis of stroke in these populations is obscure. The Stroke Investigative Research and Educational Network (SIREN) is a multicenter study involving 16 sites in West Africa. We conducted the first-ever genome-wide association study (GWAS) of stroke in indigenous Africans. METHODS Cases were consecutively recruited consenting adults (aged > 18 years) with neuroimaging-confirmed ischemic stroke. Stroke-free controls were ascertained using a locally validated Questionnaire for Verifying Stroke-Free Status. DNA genotyping with the H3Africa array was performed, and following initial quality control, GWAS datasets were imputed into the NIH Trans-Omics for Precision Medicine (TOPMed) release2 from BioData Catalyst. Furthermore, we performed fine-mapping, trans-ethnic meta-analysis, and in silico functional characterization to identify likely causal variants with a functional interpretation. RESULTS We observed genome-wide significant (P-value < 5.0E-8) SNPs associations near AADACL2 and miRNA (MIR5186) genes in chromosome 3 after adjusting for hypertension, diabetes, dyslipidemia, and cardiac status in the base model as covariates. SNPs near the miRNA (MIR4458) gene in chromosome 5 were also associated with stroke (P-value < 1.0E-6). The putative genes near AADACL2, MIR5186, and MIR4458 genes were protective and novel. SNPs associations with stroke in chromosome 2 were more than 77 kb from the closest gene LINC01854 and SNPs in chromosome 7 were more than 116 kb to the closest gene LINC01446 (P-value < 1.0E-6). In addition, we observed SNPs in genes STXBP5-AS1 (chromosome 6), GALTN9 (chromosome 12), FANCA (chromosome 16), and DLGAP1 (chromosome 18) (P-value < 1.0E-6). Both genomic regions near genes AADACL2 and MIR4458 remained significant following fine mapping. CONCLUSIONS Our findings identify potential roles of regulatory miRNA, intergenic non-coding DNA, and intronic non-coding RNA in the biology of ischemic stroke. These findings reveal new molecular targets that promise to help close the current gaps in accurate African ancestry-based genetic stroke's risk prediction and development of new targeted interventions to prevent or treat stroke.
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Affiliation(s)
- Rufus O Akinyemi
- Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Nigeria
- Center for Genomic and Precision Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Hemant K Tiwari
- Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA
| | | | - Onoja Akpa
- Center for Genomic and Precision Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Fred S Sarfo
- Department of Medicine, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Albert Akpalu
- Department of Medicine, University of Ghana Medical School, Accra, Ghana
| | - Kolawole Wahab
- Department of Medicine, University of Ilorin Teaching Hospital, Ilorin, Nigeria
| | - Reginald Obiako
- Department of Medicine, Ahmadu Bello University, Zaria, Nigeria
| | - Morenikeji Komolafe
- Department of Medicine, Obafemi Awolowo University Teaching Hospital, Ile-Ife, Nigeria
| | - Lukman Owolabi
- Department of Medicine, Aminu Kano Teaching Hospital, Kano, Nigeria
| | | | - Olga A Mamaeva
- Department of Epidemiology, School of Public Health University of Alabama at Birmingham, Birmingham, USA
| | - Brian A Halloran
- Department of Pediatrics, Volker Hall University of Alabama at Birmingham, Birmingham, USA
| | - Joshua Akinyemi
- Department of Epidemiology and Medical Statistics, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | | | - Olugbo Y Obiabo
- Delta State University/Delta State University Teaching Hospital, Oghara, Nigeria
| | - Taofik Sunmonu
- Department of Medicine, Federal Medical Centre, Ondo State, Owo, Nigeria
| | - Innocent I Chukwuonye
- Department of Medicine, Federal Medical Centre Umuahia, Abia State, Umuahia, Nigeria
| | - Oyedunni Arulogun
- Department of Health Education, Faculty of Public Health, University of Ibadan, Ibadan, Nigeria
| | | | - Abiodun Adeoye
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Atinuke Agunloye
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Okechukwu S Ogah
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Godwin Ogbole
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Adekunle Fakunle
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
- Department of Public Health, College of Health Sciences, Osun State University, Osogbo, Nigeria
| | - Ezinne Uvere
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Motunrayo M Coker
- Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Nigeria
- Genetics and Cell Biology Unit, Department of Zoology, Faculty of Science, University of Ibadan, Ibadan, Nigeria
| | - Akinkunmi Okekunle
- Department of Food and Nutrition, Seoul National University, Seoul, South Korea
| | - Osahon Asowata
- Department of Epidemiology and Medical Statistics, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Samuel Diala
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Mayowa Ogunronbi
- Department of Medicine, Federal Medical Centre, Abeokuta, Nigeria
| | - Osi Adeleye
- Department of Medicine, Federal Medical Centre, Abeokuta, Nigeria
| | - Ruth Laryea
- Department of Medicine, University of Ghana Medical School, Accra, Ghana
| | - Raelle Tagge
- Weill Institute for Neurosciences, School of Medicine, University of California San-Francisco, San Francisco, USA
| | - Sunday Adeniyi
- Department of Medicine, University of Ilorin Teaching Hospital, Ilorin, Nigeria
| | - Nathaniel Adusei
- Department of Medicine, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Wisdom Oguike
- Department of Medicine, Ahmadu Bello University, Zaria, Nigeria
| | - Paul Olowoyo
- Federal Teaching Hospital, Ido-Ekiti, Ekiti State, Nigeria
| | - Olayinka Adebajo
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Abimbola Olalere
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Olayinka Oladele
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Joseph Yaria
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Bimbo Fawale
- Department of Medicine, Obafemi Awolowo University Teaching Hospital, Ile-Ife, Nigeria
| | - Philip Ibinaye
- Department of Medicine, Ahmadu Bello University, Zaria, Nigeria
| | - Olalekan Oyinloye
- Department of Medicine, Obafemi Awolowo University Teaching Hospital, Ile-Ife, Nigeria
| | - Yaw Mensah
- Department of Medicine, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | - Omotola Oladimeji
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Josephine Akpalu
- Department of Medicine, University of Ghana Medical School, Accra, Ghana
| | - Benedict Calys-Tagoe
- Department of Medicine, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
| | | | - Adesola Ogunniyi
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Rajesh Kalaria
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Donna Arnett
- Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, USA
| | - Charles Rotimi
- Center for Genomics and Global Health, National Human Genome Research Institute, NIH, Bethesda, USA
| | - Bruce Ovbiagele
- Genetics and Cell Biology Unit, Department of Zoology, Faculty of Science, University of Ibadan, Ibadan, Nigeria
| | - Mayowa O Owolabi
- Center for Genomic and Precision Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria.
- Department of Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria.
- University College Hospital, Ibadan, Nigeria.
- Lebanese American University of Beirut, Beirut, Lebanon.
- Blossom Specialist Medical Center, Ibadan, Nigeria.
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13
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Duckett K, Williamson A, Kincaid JWR, Rainbow K, Corbin LJ, Martin HC, Eberhardt RY, Huang QQ, Hurles ME, He W, Brauner R, Delaney A, Dunkel L, Grinspon RP, Hall JE, Hirschhorn JN, Howard SR, Latronico AC, Jorge AAL, McElreavey K, Mericq V, Merino PM, Palmert MR, Plummer L, Rey RA, Rezende RC, Seminara SB, Salnikov K, Banerjee I, Lam BYH, Perry JRB, Timpson NJ, Clayton P, Chan YM, Ong KK, O’Rahilly S. Prevalence of Deleterious Variants in MC3R in Patients With Constitutional Delay of Growth and Puberty. J Clin Endocrinol Metab 2023; 108:e1580-e1587. [PMID: 37339320 PMCID: PMC10655545 DOI: 10.1210/clinem/dgad373] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 05/30/2023] [Accepted: 06/16/2023] [Indexed: 06/22/2023]
Abstract
CONTEXT The melanocortin 3 receptor (MC3R) has recently emerged as a critical regulator of pubertal timing, linear growth, and the acquisition of lean mass in humans and mice. In population-based studies, heterozygous carriers of deleterious variants in MC3R report a later onset of puberty than noncarriers. However, the frequency of such variants in patients who present with clinical disorders of pubertal development is currently unknown. OBJECTIVE This work aimed to determine whether deleterious MC3R variants are more frequently found in patients clinically presenting with constitutional delay of growth and puberty (CDGP) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH). METHODS We examined the sequence of MC3R in 362 adolescents with a clinical diagnosis of CDGP and 657 patients with nIHH, experimentally characterized the signaling properties of all nonsynonymous variants found and compared their frequency to that in 5774 controls from a population-based cohort. Additionally, we established the relative frequency of predicted deleterious variants in individuals with self-reported delayed vs normally timed menarche/voice-breaking in the UK Biobank cohort. RESULTS MC3R loss-of-function variants were infrequent but overrepresented in patients with CDGP (8/362 [2.2%]; OR = 4.17; P = .001). There was no strong evidence of overrepresentation in patients with nIHH (4/657 [0.6%]; OR = 1.15; P = .779). In 246 328 women from the UK Biobank, predicted deleterious variants were more frequently found in those self-reporting delayed (aged ≥16 years) vs normal age at menarche (OR = 1.66; P = 3.90E-07). CONCLUSION We have found evidence that functionally damaging variants in MC3R are overrepresented in individuals with CDGP but are not a common cause of this phenotype.
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Affiliation(s)
- Katie Duckett
- Wellcome-MRC Institute of Metabolic Science, Box 289, Level 4, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
| | - Alice Williamson
- Wellcome-MRC Institute of Metabolic Science, Box 289, Level 4, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
| | - John W R Kincaid
- Wellcome-MRC Institute of Metabolic Science, Box 289, Level 4, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
| | - Kara Rainbow
- Wellcome-MRC Institute of Metabolic Science, Box 289, Level 4, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
| | - Laura J Corbin
- MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK
| | - Hilary C Martin
- Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Ruth Y Eberhardt
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Qin Qin Huang
- Human Genetics, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Matthew E Hurles
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Wen He
- Division of Endocrinology, Department of Pediatrics, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115, USA
| | - Raja Brauner
- Pediatric Endocrinology Unit, Hôpital Fondation Adolphe de Rothschild and Université Paris Cité, 25 rue Manin, 75019 Paris, France
| | - Angela Delaney
- Division of Endocrinology, Department of Pediatric Medicine, St. Jude Children’s Research Hospital, 262 Danny Thomas Place MS 737, Memphis, TN 38105, USA
| | - Leo Dunkel
- Centre for Endocrinology, William Harvey Research Institute, Barts & the London Medical School, Charterhouse Square, London EC1M 6BQ, UK
| | - Romina P Grinspon
- Centro de Investigaciones Endocrinolègicas “Dr. César Bergadá” (CEDIE), CONICET–FEI–Divisièn de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330, C1425EFD Buenos Aires, Argentina
| | - Janet E Hall
- Clinical Research Branch, Division of Intramural Research, National Institute of Environmental Science, National Institute of Health, 111 TW Alexander Dr, Bldg 101 – A222, Research Triangle Park, NC 27709, USA
| | - Joel N Hirschhorn
- Division of Endocrinology, Department of Pediatrics, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115, USA
| | - Sasha R Howard
- Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK
| | - Ana C Latronico
- Departamento de Clínica Médica, Av. Dr. Arnaldo, 455 - Cerqueira César, 01246903 São Paulo - SP, Brazil
| | - Alexander A L Jorge
- Departamento de Clínica Médica, Av. Dr. Arnaldo, 455 - Cerqueira César, 01246903 São Paulo - SP, Brazil
| | - Ken McElreavey
- Institut Pasteur, Université de Paris, CNRS UMR3738, Human Developmental Genetics, F-75015 Paris, France
| | - Verónica Mericq
- Institute of Maternal and Child Research, Faculty of Medicine, University of Chile, Santa Rosa 1234, 2° piso, Santiago 8320000, Chile
| | - Paulina M Merino
- Institute of Maternal and Child Research, Faculty of Medicine, University of Chile, Santa Rosa 1234, 2° piso, Santiago 8320000, Chile
| | - Mark R Palmert
- Division of Endocrinology, The Hospital for Sick Children and Departments of Pediatrics and Physiology, University of Toronto, Toronto, ON M5G 1X8, Canada
| | - Lacey Plummer
- Massachusetts General Hospital Harvard Center for Reproductive Medicine and Reproductive Endocrine Unit, Massachusetts General Hospital, Bartlett Hall Extension, 5th Floor, 55 Fruit Street, Boston, MA 02114, USA
| | - Rodolfo A Rey
- Centro de Investigaciones Endocrinolègicas “Dr. César Bergadá” (CEDIE), CONICET–FEI–Divisièn de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Gallo 1330, C1425EFD Buenos Aires, Argentina
| | - Raíssa C Rezende
- Departamento de Clínica Médica, Av. Dr. Arnaldo, 455 - Cerqueira César, 01246903 São Paulo - SP, Brazil
| | - Stephanie B Seminara
- Massachusetts General Hospital Harvard Center for Reproductive Medicine and Reproductive Endocrine Unit, Massachusetts General Hospital, Bartlett Hall Extension, 5th Floor, 55 Fruit Street, Boston, MA 02114, USA
| | - Kathryn Salnikov
- Massachusetts General Hospital Harvard Center for Reproductive Medicine and Reproductive Endocrine Unit, Massachusetts General Hospital, Bartlett Hall Extension, 5th Floor, 55 Fruit Street, Boston, MA 02114, USA
| | - Indraneel Banerjee
- Department of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester M13 9WL, UK
| | - Brian Y H Lam
- Wellcome-MRC Institute of Metabolic Science, Box 289, Level 4, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
| | - John R B Perry
- Wellcome-MRC Institute of Metabolic Science, Box 289, Level 4, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
| | - Nicholas J Timpson
- MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK
| | - Peter Clayton
- Paediatric Endocrinology, Royal Manchester Children’s Hospital, Oxford Road, Manchester M13 9WL, UK
| | - Yee-Ming Chan
- Division of Endocrinology, Department of Pediatrics, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115, USA
| | - Ken K Ong
- MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge Biomedical Campus Box 285, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Stephen O’Rahilly
- Wellcome-MRC Institute of Metabolic Science, Box 289, Level 4, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
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14
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Chen Q, Miao Y, Xu Z, Zhang R, Yi S. miR-140 and miR-200 regulate the migratory heterogeneity of location-specific Schwann cell population. J Neurochem 2023; 166:692-704. [PMID: 37171465 DOI: 10.1111/jnc.15844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 04/14/2023] [Accepted: 04/30/2023] [Indexed: 05/13/2023]
Abstract
Schwann cells are functional cells in nerve regeneration and are commonly used as seed cells in tissue engineering. Enhanced Schwann cell migration capacity improves recovery effects, and thus, the identification of Schwann cells with greater migration ability is of great importance. In the present study, we examined the biological activities of Schwann cells collected from rat sciatic nerves (SN) and dorsal root ganglia (DRG). Observations from transwell migration assay and wound healing assay demonstrate that DRG Schwann cells migrate at a faster speed as compared with SN Schwann cells. Sequencing and bioinformatics suggest that differentially expressed genes between SN and DRG Schwann cells are associated with cell motility and migration. miR-140 and miR-200, two microRNAs (miRNAs) that are highly expressed in SN Schwann cells negatively influence Schwann cell migration and thus may be key regulators of Schwann cell phenotype. Igsf10, Plxna2, and Lcp1 are screened as candidate downstream targets of miR-140 and miR-200 based on bioinformatic analysis and their expression correlation with miRNAs. Our comparative analysis displays the unique characteristics of Schwann cells in different anatomical localizations and demonstrates that DRG Schwann cells are suitable seed cells for tissue engineering and regenerative medicine.
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Affiliation(s)
- Qianqian Chen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Yang Miao
- Department of Pharmacy, The First People's Hospital of Yancheng, Yancheng, China
| | - Zhipeng Xu
- Department of Urology, Affiliated People's Hospital of Jiangsu University, Zhenjiang First People's Hospital, Zhenjiang, China
| | - Ruirui Zhang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Sheng Yi
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
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15
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Argente J, Dunkel L, Kaiser UB, Latronico AC, Lomniczi A, Soriano-Guillén L, Tena-Sempere M. Molecular basis of normal and pathological puberty: from basic mechanisms to clinical implications. Lancet Diabetes Endocrinol 2023; 11:203-216. [PMID: 36620967 PMCID: PMC10198266 DOI: 10.1016/s2213-8587(22)00339-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/05/2022] [Accepted: 11/08/2022] [Indexed: 01/07/2023]
Abstract
Puberty is a major maturational event; its mechanisms and timing are driven by genetic determinants, but also controlled by endogenous and environmental cues. Substantial progress towards elucidation of the neuroendocrine networks governing puberty has taken place. However, key aspects of the mechanisms responsible for the precise timing of puberty and its alterations have only recently begun to be deciphered, propelled by epidemiological data suggesting that pubertal timing is changing in humans, via mechanisms that are not yet understood. By integrating basic and clinical data, we provide a comprehensive overview of current advances on the physiological basis of puberty, with a particular focus on the roles of kisspeptins and other central transmitters, the underlying molecular and endocrine mechanisms, and the pathways involved in pubertal modulation by nutritional and metabolic cues. Additionally, we have summarised molecular features of precocious and delayed puberty in both sexes, as revealed by clinical and genetic studies. This Review is a synoptic up-to-date view of how puberty is controlled and of the pathogenesis of major pubertal alterations, from both a clinical and translational perspective. We also highlight unsolved challenges that will seemingly concentrate future research efforts in this active domain of endocrinology.
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Affiliation(s)
- Jesús Argente
- Department of Pediatrics & Pediatric Endocrinology, Universidad Autónoma de Madrid, University Hospital Niño Jesús, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; IMDEA Food Institute, Madrid, Spain.
| | - Leo Dunkel
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London Medical School, London, UK
| | - Ursula B Kaiser
- Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ana C Latronico
- Developmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics, LIM42, Department of Endocrinology and Metabolism, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
| | - Alejandro Lomniczi
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA
| | - Leandro Soriano-Guillén
- Service of Pediatrics, University Hospital Fundación Jiménez Díaz, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain
| | - Manuel Tena-Sempere
- CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain; Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofia, Córdoba, Spain; Institute of Biomedicine, University of Turku, Turku, Finland.
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16
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Vezzoli V, Hrvat F, Goggi G, Federici S, Cangiano B, Quinton R, Persani L, Bonomi M. Genetic architecture of self-limited delayed puberty and congenital hypogonadotropic hypogonadism. Front Endocrinol (Lausanne) 2023; 13:1069741. [PMID: 36726466 PMCID: PMC9884699 DOI: 10.3389/fendo.2022.1069741] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 12/09/2022] [Indexed: 01/18/2023] Open
Abstract
Distinguishing between self limited delayed puberty (SLDP) and congenital hypogonadotropic hypogonadism (CHH) may be tricky as they share clinical and biochemical characteristics. and appear to lie within the same clinical spectrum. However, one is classically transient (SDLP) while the second is typically a lifetime condition (CHH). The natural history and long-term outcomes of these two conditions differ significantly and thus command distinctive approaches and management. Because the first presentation of SDLP and CHH is very similar (delayed puberty with low LH and FSH and low sex hormones), the scientific community is scrambling to identify diagnostic tests that can allow a correct differential diagnosis among these two conditions, without having to rely on the presence or absence of phenotypic red flags for CHH that clinicians anyway seem to find hard to process. Despite the heterogeneity of genetic defects so far reported in DP, genetic analysis through next-generation sequencing technology (NGS) had the potential to contribute to the differential diagnostic process between SLDP and CHH. In this review we will provide an up-to-date overview of the genetic architecture of these two conditions and debate the benefits and the bias of performing genetic analysis seeking to effectively differentiate between these two conditions.
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Affiliation(s)
- Valeria Vezzoli
- Department of Endocrine and Metabolic Diseases and Lab of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Faris Hrvat
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Giovanni Goggi
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Silvia Federici
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Biagio Cangiano
- Department of Endocrine and Metabolic Diseases and Lab of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Richard Quinton
- Department of Endocrinology, Diabetes & Metabolism, Newcastle-upon-Tyne Hospitals, Newcastle-upon-Tyne, United Kingdom
- Translational & Clinical Research Institute, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, United Kingdom
| | - Luca Persani
- Department of Endocrine and Metabolic Diseases and Lab of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Marco Bonomi
- Department of Endocrine and Metabolic Diseases and Lab of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
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17
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Zhou Y, Gao M, Jing Y, Wang X. Pan-cancer analyses reveal IGSF10 as an immunological and prognostic biomarker. Front Genet 2023; 13:1032382. [PMID: 36685968 PMCID: PMC9845414 DOI: 10.3389/fgene.2022.1032382] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 11/29/2022] [Indexed: 01/06/2023] Open
Abstract
Background: IGSF10 is a member of the immunoglobulin superfamily. Over the previous decade, growing proof has validated definitive correlations between individuals of the immunoglobulin superfamily and human diseases. However, the function of IGSF10 in pan-cancer stays unclear. We aimed to analyze the immunological and prognostic value of IGSF10 in pan-cancer. Methods: We utilized a vary of bioinformatic ways to inspect the function of IGSF10 in pan-cancer, including its correlation with prognosis, immune cell infiltration, tumor mutational burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), DNA methyltransferases, genetic alteration, drug sensitivity, etc. Results: We noticed low expression of IGSF10 in most cancer types. IGSF10 expression in tumor samples correlates with prognosis in most cancers. In most cancer types, IGSF10 expression was strongly related to immune cells infiltration, immune checkpoints, immune modulators, TMB, MSI, MMR, and DNA methyltransferases, among others. Functional enrichment analyses indicated that IGSF10 expression was involved in lymphocyte differentiation, cell molecules adhesion, etc. Furthermore, low IGSF10 expression could increase the drug sensitivity of many drugs. Conclusion: IGSF10 could serve as a novel prognostic marker and attainable immunotherapy target for several malignancies.
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Affiliation(s)
- Yongxia Zhou
- Department of Hematology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China,Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China,Tianjin’s Clinical Research Center for Cancer, Tianjin, China,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Manzhi Gao
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China,Tianjin’s Clinical Research Center for Cancer, Tianjin, China,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China
| | - Yaoyao Jing
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China,Tianjin’s Clinical Research Center for Cancer, Tianjin, China,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China,Day Ward of Tianjin Medical University Cancer Institute & Hospital, Tianjin, China
| | - Xiaofang Wang
- Department of Hematology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China,Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China,Tianjin’s Clinical Research Center for Cancer, Tianjin, China,Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China,Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China,*Correspondence: Xiaofang Wang,
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18
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Franssen D, Johansson HKL, Lopez-Rodriguez D, Lavergne A, Terwagne Q, Boberg J, Christiansen S, Svingen T, Parent AS. Perinatal exposure to the fungicide ketoconazole alters hypothalamic control of puberty in female rats. Front Endocrinol (Lausanne) 2023; 14:1140886. [PMID: 37077353 PMCID: PMC10108553 DOI: 10.3389/fendo.2023.1140886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 03/03/2023] [Indexed: 04/05/2023] Open
Abstract
INTRODUCTION Estrogenic endocrine disrupting chemicals (EDCs) such as diethylstilbestrol (DES) are known to alter the timing of puberty onset and reproductive function in females. Accumulating evidence suggests that steroid synthesis inhibitors such as ketoconazole (KTZ) or phthalates may also affect female reproductive health, however their mode of action is poorly understood. Because hypothalamic activity is very sensitive to sex steroids, we aimed at determining whether and how EDCs with different mode of action can alter the hypothalamic transcriptome and GnRH release in female rats. DESIGN Female rats were exposed to KTZ or DES during perinatal (DES 3-6-12μg/kg.d; KTZ 3-6-12mg/kg.d), pubertal or adult periods (DES 3-12-48μg/kg.d; KTZ 3-12-48mg/kg.d). RESULTS Ex vivo study of GnRH pulsatility revealed that perinatal exposure to the highest doses of KTZ and DES delayed maturation of GnRH secretion before puberty, whereas pubertal or adult exposure had no effect on GnRH pulsatility. Hypothalamic transcriptome, studied by RNAsequencing in the preoptic area and in the mediobasal hypothalamus, was found to be very sensitive to perinatal exposure to all doses of KTZ before puberty with effects persisting until adulthood. Bioinformatic analysis with Ingenuity Pathway Analysis predicted "Creb signaling in Neurons" and "IGF-1 signaling" among the most downregulated pathways by all doses of KTZ and DES before puberty, and "PPARg" as a common upstream regulator driving gene expression changes. Deeper screening ofRNAseq datasets indicated that a high number of genes regulating the activity of the extrinsic GnRH pulse generator were consistently affected by all the doses of DES and KTZ before puberty. Several, including MKRN3, DNMT3 or Cbx7, showed similar alterations in expression at adulthood. CONCLUSION nRH secretion and the hypothalamic transcriptome are highly sensitive to perinatal exposure to both DES and KTZ. The identified pathways should be exploredfurther to identify biomarkers for future testing strategies for EDC identification and when enhancing the current standard information requirements in regulation.
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Affiliation(s)
- Delphine Franssen
- Neuroendocrinology Unit, GIGA Neurosciences, University of Liège, Liège, Belgium
- *Correspondence: Delphine Franssen,
| | | | | | - Arnaud Lavergne
- GIGA-Bioinformatics, GIGA Institute, Université de Liège, Liège, Belgium
| | - Quentin Terwagne
- Neuroendocrinology Unit, GIGA Neurosciences, University of Liège, Liège, Belgium
| | - Julie Boberg
- National Food Institute, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Sofie Christiansen
- National Food Institute, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Terje Svingen
- National Food Institute, Technical University of Denmark, Kgs. Lyngby, Denmark
| | - Anne-Simone Parent
- Neuroendocrinology Unit, GIGA Neurosciences, University of Liège, Liège, Belgium
- Department of Pediatrics, University Hospital Liege, Liege, Belgium
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19
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Utilizing MALDI-TOF MS and LC-MS/MS to access serum peptidome-based biomarkers in canine oral tumors. Sci Rep 2022; 12:21641. [PMID: 36517562 PMCID: PMC9750994 DOI: 10.1038/s41598-022-26132-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 12/09/2022] [Indexed: 12/15/2022] Open
Abstract
Tumors frequently found in dogs include canine oral tumors, either cancerous or noncancerous. The bloodstream is an important route for tumor metastasis, particularly for late-stage oral melanoma (LOM) and late-stage oral squamous cell carcinoma (LOSCC). The present study aimed to investigate serum peptidome-based biomarkers of dogs with early-stage oral melanoma, LOM, LOSCC, benign oral tumors, chronic periodontitis and healthy controls, using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and liquid chromatography tandem mass spectrometry. A principal component analysis plot showed distinct clusters among all groups. Four peptides were identified, including peptidyl-prolyl cis-trans isomerase FKBP4 isoform X2 (FKBP4), steroid hormone receptor ERR1 (ESRRA or ERRA), immunoglobulin superfamily member 10 (IGSF10) and ATP-binding cassette subfamily B member 5 (ABCB5). FKBP4, ESRRA and ABCB5 were found to be overexpressed in both LOM and LOSCC, whereas IGSF10 expression was markedly increased in LOSCC only. These four proteins also played a crucial role in numerous pathways of cancer metastasis and showed a strong relationship with chemotherapy drugs. In conclusion, this study showed rapid screening of canine oral tumors using serum and MALDI-TOF MS. In addition, potential serum peptidome-based biomarker candidates for LOM and LOSCC were identified.
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20
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Lippincott MF, Xu W, Smith AA, Miao X, Lafont A, Shennib O, Farley GJ, Sabbagh R, Delaney A, Stamou M, Plummer L, Salnikov K, Georgopoulos NA, Mericq V, Quinton R, Mau-Them FT, Nambot S, Hamad A, Brittain H, Tooze RS, Calpena E, Wilkie AOM, Willems M, Crowley WF, Balasubramanian R, Lamarche-Vane N, Davis EE, Seminara SB. The p190 RhoGAPs, ARHGAP35, and ARHGAP5 are implicated in GnRH neuronal development: Evidence from patients with idiopathic hypogonadotropic hypogonadism, zebrafish, and in vitro GAP activity assay. Genet Med 2022; 24:2501-2515. [PMID: 36178483 PMCID: PMC9730938 DOI: 10.1016/j.gim.2022.08.025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 08/24/2022] [Accepted: 08/24/2022] [Indexed: 12/14/2022] Open
Abstract
PURPOSE The study aimed to identify novel genes for idiopathic hypogonadotropic hypogonadism (IHH). METHODS A cohort of 1387 probands with IHH underwent exome sequencing and de novo, familial, and cohort-wide investigations. Functional studies were performed on 2 p190 Rho GTPase-activating proteins (p190 RhoGAP), ARHGAP35 and ARHGAP5, which involved in vivo modeling in larval zebrafish and an in vitro p190A-GAP activity assay. RESULTS Rare protein-truncating variants (PTVs; n = 5) and missense variants in the RhoGAP domain (n = 7) in ARHGAP35 were identified in IHH cases (rare variant enrichment: PTV [unadjusted P = 3.1E-06] and missense [adjusted P = 4.9E-03] vs controls). Zebrafish modeling using gnrh3:egfp phenotype assessment showed that mutant larvae with deficient arhgap35a, the predominant ARHGAP35 paralog in the zebrafish brain, display decreased GnRH3-GFP+ neuronal area, a readout for IHH. In vitro GAP activity studies showed that 1 rare missense variant [ARHGAP35 p.(Arg1284Trp)] had decreased GAP activity. Rare PTVs (n = 2) also were discovered in ARHGAP5, a paralog of ARHGAP35; however, arhgap5 zebrafish mutants did not display significant GnRH3-GFP+ abnormalities. CONCLUSION This study identified ARHGAP35 as a new autosomal dominant genetic driver for IHH and ARHGAP5 as a candidate gene for IHH. These observations suggest a novel role for the p190 RhoGAP proteins in GnRH neuronal development and integrity.
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Affiliation(s)
| | - Wanxue Xu
- Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA
| | - Abigail A Smith
- Department of Pediatrics and Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL; Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
| | - Xinyu Miao
- Cancer Research Program, Research Institute of the McGill University Health Centre, Department of Anatomy and Cell Biology, McGill University, Montréal, Quebec, Canada
| | - Agathe Lafont
- Center for Human Disease Modeling, Duke University Medical Center, Durham, NC
| | - Omar Shennib
- Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
| | - Gordon J Farley
- Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA
| | - Riwa Sabbagh
- Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA
| | - Angela Delaney
- Intramural Research Program, National Institutes of Health, Bethesda, MD
| | - Maria Stamou
- Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA
| | - Lacey Plummer
- Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA
| | - Kathryn Salnikov
- Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA
| | - Neoklis A Georgopoulos
- Division of Endocrinology-Department of Internal Medicine, University of Patras School of Health Sciences, Rio-Patras, Greece
| | - Veronica Mericq
- Instituto de Investigaciones Materno Infantil (IDIMI), University of Chile, Santiago, Chile
| | - Richard Quinton
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Frederic Tran Mau-Them
- Functional Unit 6254 Innovation in Genomic Diagnosis of Rare Diseases, CHU Dijon Bourgogne, Dijon, France
| | - Sophie Nambot
- Centre de Référence Maladies Rares « Anomalies du Développement Et Syndrome Malformatifs » de L'Est, Hôpital D'Enfants, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France
| | - Asma Hamad
- Department of Clinical Genetics, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, United Kingdom
| | - Helen Brittain
- Department of Clinical Genetics, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, United Kingdom
| | - Rebecca S Tooze
- Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Eduardo Calpena
- Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Andrew O M Wilkie
- Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Marjolaine Willems
- Medical Genetic Department for Rare Diseases and Personalized Medicine, Reference Center AD SOOR, AnDDI-RARE, Groupe DI, Inserm U1298, INM, Montpellier University, Centre Hospitalier Universitaire de Montpellier, Montpellier, France
| | | | | | - Nathalie Lamarche-Vane
- Cancer Research Program, Research Institute of the McGill University Health Centre, Department of Anatomy and Cell Biology, McGill University, Montréal, Quebec, Canada
| | - Erica E Davis
- Department of Pediatrics and Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL; Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
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21
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Saengkaew T, Howard SR. Genetics of pubertal delay. Clin Endocrinol (Oxf) 2022; 97:473-482. [PMID: 34617615 PMCID: PMC9543006 DOI: 10.1111/cen.14606] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/29/2021] [Accepted: 10/04/2021] [Indexed: 12/23/2022]
Abstract
The timing of pubertal development is strongly influenced by the genetic background, and clinical presentations of delayed puberty are often found within families with clear patterns of inheritance. The discovery of the underlying genetic regulators of such conditions, in recent years through next generation sequencing, has advanced the understanding of the pathogenesis of disorders of pubertal timing and the potential for genetic testing to assist diagnosis for patients with these conditions. This review covers the significant advances in the understanding of the biological mechanisms of delayed puberty that have occurred in the last two decades.
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Affiliation(s)
- Tansit Saengkaew
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and DentistryQueen Mary University of LondonLondonUK
- Endocrinology Unit, Department of Paediatrics, Faculty of MedicinePrince of Songkla UniversitySongkhlaThailand
| | - Sasha R. Howard
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and DentistryQueen Mary University of LondonLondonUK
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22
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Showpnil IA, Selich-Anderson J, Taslim C, Boone MA, Crow JC, Theisen ER, Lessnick SL. EWS/FLI mediated reprogramming of 3D chromatin promotes an altered transcriptional state in Ewing sarcoma. Nucleic Acids Res 2022; 50:9814-9837. [PMID: 36124657 PMCID: PMC9508825 DOI: 10.1093/nar/gkac747] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 08/10/2022] [Accepted: 08/23/2022] [Indexed: 12/13/2022] Open
Abstract
Ewing sarcoma is a prototypical fusion transcription factor-associated pediatric cancer that expresses EWS/FLI or a highly related FET/ETS chimera. EWS/FLI dysregulates transcription to induce and maintain sarcomagenesis, but the mechanisms utilized are not fully understood. We therefore sought to define the global effects of EWS/FLI on chromatin conformation and transcription in Ewing sarcoma cells using a well-validated ‘knock-down/rescue’ model of EWS/FLI function in combination with next generation sequencing assays to evaluate how the chromatin landscape changes with loss, and recovery, of EWS/FLI expression. We found that EWS/FLI (and EWS/ERG) genomic localization is largely conserved across multiple patient-derived Ewing sarcoma cell lines. This EWS/FLI binding signature is associated with establishment of topologically-associated domain (TAD) boundaries, compartment activation, enhancer-promoter looping that involve both intra- and inter-TAD interactions, and gene activation. In addition, EWS/FLI co-localizes with the loop-extrusion factor cohesin to promote chromatin loops and TAD boundaries. Importantly, local chromatin features provide the basis for transcriptional heterogeneity in regulation of direct EWS/FLI target genes across different Ewing sarcoma cell lines. These data demonstrate a key role of EWS/FLI in mediating genome-wide changes in chromatin configuration and support the notion that fusion transcription factors serve as master regulators of three-dimensional reprogramming of chromatin.
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Affiliation(s)
- Iftekhar A Showpnil
- Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.,Molecular, Cellular, and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH 43210, USA
| | - Julia Selich-Anderson
- Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Cenny Taslim
- Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Megann A Boone
- Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.,Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210, USA
| | - Jesse C Crow
- Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA
| | - Emily R Theisen
- Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.,Molecular, Cellular, and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH 43210, USA.,Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210, USA.,Department of Pediatrics, The Ohio State University, Columbus, OH 43210, USA
| | - Stephen L Lessnick
- Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.,Molecular, Cellular, and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH 43210, USA.,Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH 43210, USA.,Department of Pediatrics, The Ohio State University, Columbus, OH 43210, USA.,Division of Pediatric Heme/Onc/BMT, The Ohio State University College of Medicine, Columbus, OH 43210, USA
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23
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Fogarty CE, Suwansa-ard S, Phan P, McManus DP, Duke MG, Wyeth RC, Cummins SF, Wang T. Identification of Putative Neuropeptides That Alter the Behaviour of Schistosoma mansoni Cercariae. BIOLOGY 2022; 11:biology11091344. [PMID: 36138823 PMCID: PMC9495596 DOI: 10.3390/biology11091344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/31/2022] [Accepted: 09/09/2022] [Indexed: 11/16/2022]
Abstract
Elucidating the infectivity of Schistosoma mansoni, one of the main etiological agents of human schistosomiasis, requires an improved understanding of the behavioural mechanisms of cercariae, the non-feeding mammalian infective stage. This study investigated the presence and effect of cercariae-derived putative neuropeptides on cercarial behaviour when applied externally. Cercariae were peptidomically analysed and 11 neuropeptide precursor proteins, all of which were specific to the Schistosoma genus and most of which highly expressed in the cercarial stage, were identified in cercariae for the first time. Protein–protein interaction analysis predicted the interaction of various neuropeptide precursors (e.g., Sm-npp-30, Sm-npp-33, Sm-npp-35) with cercarial structural proteins (e.g., myosin heavy chain and titin). In total, nine putative neuropeptides, selected based on their high hydrophobicity and small size (~1 kilodalton), were tested on cercariae (3 mg/mL) in acute exposure (1 min) and prolonged exposure (360 min) behavioural bioassays. The peptides AAYMDLPW-NH2, NRKIDQSFYSYY-NH2, FLLALPSP-OH, and NYLWDTRL-NH2 stimulated acute increases in cercarial spinning, stopping, and directional change during active states. However, only NRKIDQSFYSYY-NH2 caused the same behavioural changes at a lower concentration (0.1 mg/mL). After prolonged exposure, AAYMDLPW-NH2 and NYLWDTRL-NH2 caused increasing passive behaviour and NRKIDQSFYSYY-NH2 caused increasing body-first and head-pulling movements. These findings characterise behaviour-altering novel putative neuropeptides, which may inform future biocontrol innovations to prevent human schistosomiasis.
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Affiliation(s)
- Conor E. Fogarty
- Centre for Bioinnovation, University of the Sunshine Coast, Maroochydore, QLD 4556, Australia
- School of Science, Technology and Engineering, University of the Sunshine Coast, Maroochydore, QLD 4556, Australia
| | - Saowaros Suwansa-ard
- Centre for Bioinnovation, University of the Sunshine Coast, Maroochydore, QLD 4556, Australia
- School of Science, Technology and Engineering, University of the Sunshine Coast, Maroochydore, QLD 4556, Australia
| | - Phong Phan
- Centre for Bioinnovation, University of the Sunshine Coast, Maroochydore, QLD 4556, Australia
- School of Science, Technology and Engineering, University of the Sunshine Coast, Maroochydore, QLD 4556, Australia
| | - Donald P. McManus
- QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
| | - Mary G. Duke
- QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia
| | - Russell C. Wyeth
- Department of Biology, St. Francis Xavier University, Antigonish, NS B2G 2W5, Canada
| | - Scott F. Cummins
- Centre for Bioinnovation, University of the Sunshine Coast, Maroochydore, QLD 4556, Australia
- School of Science, Technology and Engineering, University of the Sunshine Coast, Maroochydore, QLD 4556, Australia
| | - Tianfang Wang
- Centre for Bioinnovation, University of the Sunshine Coast, Maroochydore, QLD 4556, Australia
- School of Science, Technology and Engineering, University of the Sunshine Coast, Maroochydore, QLD 4556, Australia
- Correspondence:
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24
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Xu NY, Liu ZY, Yang QM, Bian PP, Li M, Zhao X. Genomic Analyses for Selective Signatures and Genes Involved in Hot Adaptation Among Indigenous Chickens From Different Tropical Climate Regions. Front Genet 2022; 13:906447. [PMID: 35979430 PMCID: PMC9377314 DOI: 10.3389/fgene.2022.906447] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 06/15/2022] [Indexed: 11/13/2022] Open
Abstract
Climate change, especially weather extremes like extreme cold or extreme hot, is a major challenge for global livestock. One of the animal breeding goals for sustainable livestock production should be to breed animals with excellent climate adaptability. Indigenous livestock and poultry are well adapted to the local climate, and they are good resources to study the genetic footprints and mechanism of the resilience to weather extremes. In order to identify selection signatures and genes that might be involved in hot adaptation in indigenous chickens from different tropical climates, we conducted a genomic analysis of 65 indigenous chickens that inhabit different climates. Several important unique positively selected genes (PSGs) were identified for each local chicken group by the cross-population extended haplotype homozygosity (XP-EHH). These PSGs, verified by composite likelihood ratio, genetic differentiation index, nucleotide diversity, Tajima’s D, and decorrelated composite of multiple signals, are related to nerve regulation, vascular function, immune function, lipid metabolism, kidney development, and function, which are involved in thermoregulation and hot adaptation. However, one common PSG was detected for all three tropical groups of chickens via XP-EHH but was not confirmed by other five types of selective sweep analyses. These results suggest that the hot adaptability of indigenous chickens from different tropical climate regions has evolved in parallel by taking different pathways with different sets of genes. The results from our study have provided reasonable explanations and insights for the rapid adaptation of chickens to diverse tropical climates and provide practical values for poultry breeding.
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Affiliation(s)
- Nai-Yi Xu
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Zhen-Yu Liu
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Qi-Meng Yang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Pei-Pei Bian
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Ming Li
- Department of Biology, University of Konstanz, Konstanz, Germany
| | - Xin Zhao
- Department of Animal Science, McGill University, Montreal, QC, Canada
- *Correspondence: Xin Zhao,
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25
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Tellman TV, Dede M, Aggarwal VA, Salmon D, Naba A, Farach-Carson MC. Systematic Analysis of Actively Transcribed Core Matrisome Genes Across Tissues and Cell Phenotypes. Matrix Biol 2022; 111:95-107. [PMID: 35714875 DOI: 10.1016/j.matbio.2022.06.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 05/20/2022] [Accepted: 06/13/2022] [Indexed: 11/16/2022]
Abstract
The extracellular matrix (ECM) is a highly dynamic, well-organized acellular network of tissue-specific biomolecules, that can be divided into structural or core ECM proteins and ECM-associated proteins. The ECM serves as a blueprint for organ development and function and, when structurally altered through mutation, altered expression, or degradation, can lead to debilitating syndromes that often affect one tissue more than another. Cross-referencing the FANTOM5 SSTAR (Semantic catalog of Samples, Transcription initiation And Regulators) and the defined catalog of core matrisome ECM (glyco)proteins, we conducted a comprehensive analysis of 511 different human samples to annotate the context-specific transcription of the individual components of the defined matrisome. Relative log expression normalized SSTAR cap analysis gene expression peak data files were downloaded from the FANTOM5 online database and filtered to exclude all cell lines and diseased tissues. Promoter-level expression values were categorized further into eight core tissue systems and three major ECM categories: proteoglycans, glycoproteins, and collagens. Hierarchical clustering and correlation analyses were conducted to identify complex relationships in promoter-driven gene expression activity. Integration of the core matrisome and curated FANTOM5 SSTAR data creates a unique tool that provides insight into the promoter-level expression of ECM-encoding genes in a tissue- and cell-specific manner. Unbiased clustering of cap analysis gene expression peak data reveals unique ECM signatures within defined tissue systems. Correlation analysis among tissue systems exposes both positive and negative correlation of ECM promoters with varying levels of significance. This tool can be used to provide new insight into the relationships between ECM components and tissues and can inform future research on the ECM in human disease and development. We invite the matrix biology community to continue to explore and discuss this dataset as part of a larger and continuing conversation about the human ECM. An interactive web tool can be found at matrixpromoterome.github.io along with additional resources that can be found at dx.doi.org/10.6084/m9.figshare.19794481 (figures) and https://figshare.com/s/e18ecbc3ae5aaf919b78 (python notebook).
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Affiliation(s)
- Tristen V Tellman
- Department of Diagnostic & Biomedical Sciences, University of Texas Health Science Center at Houston School of Dentistry, 1941 East Road, BBS-4220, Houston, TX 77054, USA
| | - Merve Dede
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, P.O. Box 301402 Houston, TX 77230, USA
| | - Vikram A Aggarwal
- Departments of BioSciences and Bioengineering, Rice University, 6100 Main St., Houston, TX 77005, USA
| | - Duncan Salmon
- Department of Diagnostic & Biomedical Sciences, University of Texas Health Science Center at Houston School of Dentistry, 1941 East Road, BBS-4220, Houston, TX 77054, USA
| | - Alexandra Naba
- Department of Physiology and Biophysics, University of Illinois at Chicago, 835 S. Wolcott, Rm E202 (MC901), Chicago, IL 60612, USA
| | - Mary C Farach-Carson
- Department of Diagnostic & Biomedical Sciences, University of Texas Health Science Center at Houston School of Dentistry, 1941 East Road, BBS-4220, Houston, TX 77054, USA.; Departments of BioSciences and Bioengineering, Rice University, 6100 Main St., Houston, TX 77005, USA.; Center for Theoretical Biological Physics, Rice University, 6100 Main St., Houston, TX 77005, USA..
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26
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Abstract
Pediatric endocrinologists often evaluate and treat youth with delayed puberty. Stereotypically, these patients are 14-year-old young men who present due to lack of pubertal development. Concerns about stature are often present, arising from gradual shifts to lower height percentiles on the population-based, cross-sectional curves. Fathers and/or mothers may have also experienced later than average pubertal onset. In this review, we will discuss a practical clinical approach to the evaluation and management of youth with delayed puberty, including the differential diagnosis and key aspects of evaluation and management informed by recent review of the existing literature. We will also discuss scenarios that pose additional clinical challenges, including: (1) the young woman whose case poses questions regarding how presentation and approach differs for females vs males; (2) the 14-year-old female or 16-year-old young man who highlight the need to reconsider the most likely diagnoses, including whether idiopathic delayed puberty can still be considered constitutional delay of growth and puberty at such late ages; and finally (3) the 12- to 13-year-old whose presentation raises questions about whether age cutoffs for the diagnosis and treatment of delayed puberty should be adjusted downward to coincide with the earlier onset of puberty in the general population.
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Affiliation(s)
- Jennifer Harrington
- Division of Endocrinology, Women's and Children's Health Network, North Adelaide, 5006, Australia
- Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, 5000, Australia
| | - Mark R Palmert
- Division of Endocrinology, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada
- Departments of Pediatrics and Physiology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada
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27
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Ogawa S, Yamamoto N, Hagio H, Oka Y, Parhar IS. Multiple gonadotropin-releasing hormone systems in non-mammalian vertebrates: Ontogeny, anatomy, and physiology. J Neuroendocrinol 2022; 34:e13068. [PMID: 34931380 DOI: 10.1111/jne.13068] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 11/17/2021] [Accepted: 11/19/2021] [Indexed: 01/08/2023]
Abstract
Three paralogous genes for gonadotropin-releasing hormone (GnRH; gnrh1, gnrh2, and gnrh3) and GnRH receptors exist in non-mammalian vertebrates. However, there are some vertebrate species in which one or two of these paralogous genes have become non-functional during evolution. The developmental migration of GnRH neurons in the brain is evolutionarily conserved in mammals, reptiles, birds, amphibians, and jawed teleost fish. The three GnRH paralogs have specific expression patterns in the brain and originate from multiple sites. In acanthopterygian teleosts (medaka, cichlid, etc.), the preoptic area (POA)-GnRH1 and terminal nerve (TN)-GnRH3 neuronal types originate from the olfactory regions. In other fish species (zebrafish, goldfish and salmon) with only two GnRH paralogs (GnRH2 and GnRH3), the TN- and POA-GnRH3 neuronal types share the same olfactory origin. However, the developmental origin of midbrain (MB)-GnRH2 neurons is debatable between mesencephalic or neural crest site. Each GnRH system has distinctive anatomical and physiological characteristics, and functions differently. The POA-GnRH1 neurons are hypophysiotropic in nature and function in the neuroendocrine control of reproduction. The non-hypophysiotropic GnRH2/GnRH3 neurons probably play neuromodulatory roles in metabolism (MB-GnRH2) and the control of motivational state for sexual behavior (TN-GnRH3).
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Affiliation(s)
- Satoshi Ogawa
- Jeffrey Cheah School of Medicine & Health Sciences, Monash University Malaysia, Selangor, Malaysia
| | - Naoyuki Yamamoto
- Laboratory of Fish Biology, Department of Animal Sciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan
| | - Hanako Hagio
- Laboratory of Fish Biology, Department of Animal Sciences, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan
- Institute for Advanced Research, Nagoya University, Nagoya, Japan
| | - Yoshitaka Oka
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
| | - Ishwar S Parhar
- Jeffrey Cheah School of Medicine & Health Sciences, Monash University Malaysia, Selangor, Malaysia
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28
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Bando H, Urai S, Kanie K, Sasaki Y, Yamamoto M, Fukuoka H, Iguchi G, Camper SA. Novel genes and variants associated with congenital pituitary hormone deficiency in the era of next-generation sequencing. Front Endocrinol (Lausanne) 2022; 13:1008306. [PMID: 36237189 PMCID: PMC9551393 DOI: 10.3389/fendo.2022.1008306] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 09/09/2022] [Indexed: 01/07/2023] Open
Abstract
Combined pituitary hormone deficiency (CPHD) is not a rare disorder, with a frequency of approximately 1 case per 4,000 live births. However, in most cases, a genetic diagnosis is not available. Furthermore, the diagnosis is challenging because no clear correlation exists between the pituitary hormones affected and the gene(s) responsible for the disorder. Next-generation sequencing (NGS) has recently been widely used to identify novel genes that cause (or putatively cause) CPHD. This review outlines causative genes for CPHD that have been newly reported in recent years. Moreover, novel variants of known CPHD-related genes (POU1F1 and GH1 genes) that contribute to CPHD through unique mechanisms are also discussed in this review. From a clinical perspective, variants in some of the recently identified causative genes result in extra-pituitary phenotypes. Clinical research on the related symptoms and basic research on pituitary formation may help in inferring the causative gene(s) of CPHD. Future NGS analysis of a large number of CPHD cases may reveal new genes related to pituitary development. Clarifying the causative genes of CPHD may help to understand the process of pituitary development. We hope that future innovations will lead to the identification of genes responsible for CPHD and pituitary development.
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Affiliation(s)
- Hironori Bando
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Hospital, Kobe, Japan
- *Correspondence: Hironori Bando,
| | - Shin Urai
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University School of Medicine, Kobe, Japan
| | - Keitaro Kanie
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Hospital, Kobe, Japan
| | - Yuriko Sasaki
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Hospital, Kobe, Japan
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University School of Medicine, Kobe, Japan
| | - Masaaki Yamamoto
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Hospital, Kobe, Japan
| | - Hidenori Fukuoka
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Hospital, Kobe, Japan
| | - Genzo Iguchi
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Hospital, Kobe, Japan
- Division of Biosignal Pathophysiology, Kobe University Graduate School of Medicine, Kobe, Japan
- Medical Center for Student Health, Kobe University, Kobe, Japan
| | - Sally A. Camper
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, United States
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29
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Abstract
Puberty marks the end of childhood and is a period when individuals undergo physiological and psychological changes to achieve sexual maturation and fertility. The onset of puberty is first detected as an increase in pulsatile secretion of gonadotropin-releasing hormone (GnRH). Pubertal onset is regulated by genetic, nutritional, environmental, and socio-economic factors. Disturbances affecting pubertal timing result in adverse health conditions later in life. Human genetic studies show that around 50-80% of the variation in pubertal onset is genetically determined. The genetic control of pubertal timing has been a field of active investigation in attempt to better understand the neuroendocrine control of this relevant period of life. Large populational studies and patient cohort-based studies have provided insights into the genetic regulation of pubertal onset. In this review, we discuss these discoveries and discuss potential mechanisms for how implicated genes may affect pubertal timing.
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Affiliation(s)
- Alessandra Mancini
- Department of Medicine, Harvard Medical School, Division of Endocrinology Diabetes and Hypertension, Brigham and Women's Hospital, Boston, USA.
| | - John C Magnotto
- Department of Medicine, Harvard Medical School, Division of Endocrinology Diabetes and Hypertension, Brigham and Women's Hospital, Boston, USA.
| | - Ana Paula Abreu
- Department of Medicine, Harvard Medical School, Division of Endocrinology Diabetes and Hypertension, Brigham and Women's Hospital, Boston, USA.
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30
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Fontana L, Garzia E, Marfia G, Galiano V, Miozzo M. Epigenetics of functional hypothalamic amenorrhea. Front Endocrinol (Lausanne) 2022; 13:953431. [PMID: 36034425 PMCID: PMC9415998 DOI: 10.3389/fendo.2022.953431] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
Functional hypothalamic amenorrhea (FHA) is a temporary infertility characterized by the suppression of the hypothalamic-pituitary-gonadal (HPG) axis, induced by the inhibition of the hypothalamic pulsatile secretion of the gonadotropin-releasing hormone (GnRH), in the presence of stressors, including eating disorders, excessive exercise, and psychological distress. Although the stressful factors that may lead to FHA are well-established, little is known about the inter-individual variability in response to stress and the consequent inhibition of the HPG axis. Not all women, indeed, manifest FHA in presence of stressful conditions. Recent studies highlighted a genetic contribution to FHA. Rare or polymorphic variants in genes that control the development and/or function of GnRH neurons may contribute, indeed, to the adaptability of the reproductive axis to stress factors. Also epigenetic changes have been associated with different pathways involved in the HPG axis and therefore, take part in FHA and confer a personal predisposition to anovulation consequent to a stressful event, or represent biological markers of response to stress. This review summarizes recent advances in the identification of the contribution of (epi)genetics to FHA and to long-term complications of functional amenorrhea, and reports insights into the involvement of additional genetic loci in FHA development on the bases of the clinical and molecular overlap with other gynecological and/or psychological conditions. Finally, we describe the promising application of induced pluripotent stem cells (iPSCs) as a new approach to investigate the molecular pathways involved in FHA.
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Affiliation(s)
- L. Fontana
- Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
- Unit of Medical Genetics, ASST Santi Paolo e Carlo, Milan, Italy
| | - E. Garzia
- Reproductive Medicine Unit, Department of Mother and Child, San Paolo Hospital, ASST Santi Paolo e Carlo, Milan, Italy
- Aerospace Medicine Institute “A. Mosso”, Italian Air Force, Milan, Italy
| | - G. Marfia
- Aerospace Medicine Institute “A. Mosso”, Italian Air Force, Milan, Italy
- Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - V. Galiano
- Reproductive Medicine Unit, Department of Mother and Child, San Paolo Hospital, ASST Santi Paolo e Carlo, Milan, Italy
| | - M. Miozzo
- Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
- Unit of Medical Genetics, ASST Santi Paolo e Carlo, Milan, Italy
- *Correspondence: M. Miozzo,
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31
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Abstract
The diagnostic suspicion of congenital central hypogonadism is based on clinical signs. Biochemical confirmation is challenging, especially after the postnatal activation stage of the hypothalamic-pituitary-testicular axis. Sertoli cell markers, like AMH and inhibin B, have become useful tools for the diagnosis of male central hypogonadism during childhood. Different mechanisms can participate in the aetiopathogenesis of central hypogonadism, leading to a deficiency in the production of gonadotrophins. Advances in genetic studies, mainly next generation sequencing techniques, have allowed the discovery of a large number of genes related to central hypogonadism. However, a causal variant is found in approximately half of the patients. Central hypogonadism has been classically described as a pathology with variable expressivity and incomplete penetrance. Currently, these characteristics are known to be partially explained by the presence of oligogenicity, that is the participation of variants in more than one gene in the aetiology of central hypogonadism in the same patient.
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Affiliation(s)
- Romina P Grinspon
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET - FEI - División de, Endocrinología, Hospital de Niños Ricardo Gutiérrez, C1425EFD, Buenos Aires, Argentina.
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32
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Faienza MF, Urbano F, Moscogiuri LA, Chiarito M, De Santis S, Giordano P. Genetic, epigenetic and enviromental influencing factors on the regulation of precocious and delayed puberty. Front Endocrinol (Lausanne) 2022; 13:1019468. [PMID: 36619551 PMCID: PMC9813382 DOI: 10.3389/fendo.2022.1019468] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 12/08/2022] [Indexed: 12/24/2022] Open
Abstract
The pubertal development onset is controlled by a network of genes that regulate the gonadotropin releasing hormone (GnRH) pulsatile release and the subsequent increase of the circulating levels of pituitary gonadotropins that activate the gonadal function. Although the transition from pre-pubertal condition to puberty occurs physiologically in a delimited age-range, the inception of pubertal development can be anticipated or delayed due to genetic and epigenetic changes or environmental conditions. Most of the genetic and epigenetic alterations concern genes which encode for kisspeptin, GnRH, LH, FSH and their receptor, which represent crucial factors of the hypothalamic-pituitary-gonadal (HPG) axis. Recent data indicate a central role of the epigenome in the regulation of genes in the hypothalamus and pituitary that could mediate the flexibility of pubertal timing. Identification of epigenetically regulated genes, such as Makorin ring finger 3 (MKRN3) and Delta-like 1 homologue (DLK1), respectively responsible for the repression and the activation of pubertal development, provides additional evidence of how epigenetic variations affect pubertal timing. This review aims to investigate genetic, epigenetic, and environmental factors responsible for the regulation of precocious and delayed puberty.
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Affiliation(s)
- Maria Felicia Faienza
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, Bari, Italy
- Giovanni XXIII Pediatric Hospital, Bari, Italy
- *Correspondence: Maria Felicia Faienza,
| | | | | | | | - Stefania De Santis
- Department of Pharmacy-Pharmaceutical Science, University of Bari “Aldo Moro”, Bari, Italy
| | - Paola Giordano
- Giovanni XXIII Pediatric Hospital, Bari, Italy
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Bari, Italy
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33
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Abstract
Idiopathic hypogonadotropic hypogonadism (IHH) is a group of rare developmental disorders characterized by low gonadotropin levels in the face of low sex steroid hormone concentrations. IHH is practically divided into two major groups according to the olfactory function: normal sense of smell (normosmia) nIHH, and reduced sense of smell (hyposmia/anosmia) Kallmann syndrome (KS). Although mutations in more than 50 genes have been associated with IHH so far, only half of those cases were explained by gene mutations. Various combinations of deleterious variants in different genes as causes of IHH have been increasingly recognized (Oligogenic etiology). In addition to the complexity of inheritance patterns, the spontaneous or sex steroid-induced clinical recovery from IHH, which is seen in approximately 10–20% of cases, blurs further the phenotype/genotype relationship in IHH, and poses challenging steps in new IHH gene discovery. Beyond helping for clinical diagnostics, identification of the genetic mutations in the pathophysiology of IHH is hoped to shed light on the central governance of the hypothalamo-pituitary-gonadal axis through life stages. This review aims to summarize the genetic etiology of IHH and discuss the clinical and physiological ramifications of the gene mutations.
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34
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Saengkaew T, Ruiz-Babot G, David A, Mancini A, Mariniello K, Cabrera CP, Barnes MR, Dunkel L, Guasti L, Howard SR. Whole exome sequencing identifies deleterious rare variants in CCDC141 in familial self-limited delayed puberty. NPJ Genom Med 2021; 6:107. [PMID: 34930920 PMCID: PMC8688425 DOI: 10.1038/s41525-021-00274-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022] Open
Abstract
Developmental abnormalities of the gonadotropin-releasing hormone (GnRH) neuronal network result in a range of conditions from idiopathic hypogonadotropic hypogonadism to self-limited delayed puberty. We aimed to discover important underlying regulators of self-limited delayed puberty through interrogation of GnRH pathways. Whole exome sequencing (WES) data consisting of 193 individuals, from 100 families with self-limited delayed puberty, was analysed using a virtual panel of genes related to GnRH development and function (n = 12). Five rare predicted deleterious variants in Coiled-Coil Domain Containing 141 (CCDC141) were identified in 21 individuals from 6 families (6% of the tested cohort). Homology modeling predicted all five variants to be deleterious. CCDC141 mutant proteins showed atypical subcellular localization associated with abnormal distribution of acetylated tubulin, and expression of mutants resulted in a significantly delayed cell migration, demonstrated in transfected HEK293 cells. These data identify mutations in CCDC141 as a frequent finding in patients with self-limited delayed puberty. The mis-localization of acetylated tubulin and reduced cell migration seen with mutant CCDC141 suggests a role of the CCDC141-microtubule axis in GnRH neuronal migration, with heterozygous defects potentially impacting the timing of puberty.
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Affiliation(s)
- Tansit Saengkaew
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.,Endocrinology Unit, Department of Paediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Gerard Ruiz-Babot
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Alessia David
- Department of Life Sciences, Centre for Integrative Systems Biology and Bioinformatics, Imperial College London, London, UK
| | - Alessandra Mancini
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Katia Mariniello
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Claudia P Cabrera
- Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.,NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Michael R Barnes
- Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.,NIHR Barts Cardiovascular Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Leo Dunkel
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Leonardo Guasti
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Sasha R Howard
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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35
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Sun SS, Wang RX. Molecular diagnosis of Kallmann syndrome with diabetes by whole exome sequencing and bioinformatic approaches. World J Diabetes 2021; 12:2058-2072. [PMID: 35047120 PMCID: PMC8696644 DOI: 10.4239/wjd.v12.i12.2058] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/07/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Kallmann syndrome (KS) is a hypogonadotropic hypogonadism accompanied by anosmia or hyposmia. It is associated with the low secretion of gonadotropins which can lead to other abnormal endocrine metabolism disorders such as diabetes. Through genetic and molecular biological methods, more than 10 KS pathogenic genes have been found.
AIM To identify the existing mutation sites of KS with diabetes and reveal the relationship between genotype and phenotype.
METHODS We studied KS pathogenesis through high-throughput exome sequencing on four diabetes’ patients with KS for screening the potential pathogenic sites and exploring the genotype-phenotype correlation. Clinical data and peripheral blood samples were collected from the patients. White blood cells were separated and genomic DNA was extracted. High-throughput sequencing of all exons in the candidate pathogenic genes of probands was performed, and the results obtained were analyzed.
RESULTS Sequencing revealed mutations in the KLB p.T313M, ANOS1 p.C172F, and IGSF10 gene (p.Lys1819Arg and p.Arg1035Thr) at different sites, which may have been associated with disease onset.
CONCLUSION The diagnosis of KS is challenging, especially in early puberty, and the clinical manifestations reflect physical delays in development and puberty. Timely diagnosis and treatment can induce puberty, thereby improving sexual, bone, metabolic and mental health.
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Affiliation(s)
- Shuang-Shuang Sun
- Clinical Lab, Shanxi Provincial People's Hospital, Taiyuan 030012, Shanxi Province, China
| | - Rui-Xue Wang
- Clinical Lab, Shanxi Provincial People's Hospital, Taiyuan 030012, Shanxi Province, China
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36
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Liu D, Liu Y, Zhang X, Wang Y, Zhang C, Zheng S. An Exploration of Mutagenesis in a Family with Cleidocranial Dysplasia without RUNX2 Mutation. Front Genet 2021; 12:748111. [PMID: 34737766 PMCID: PMC8560734 DOI: 10.3389/fgene.2021.748111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 09/29/2021] [Indexed: 11/22/2022] Open
Abstract
Cleidocranial dysplasia (CCD) is an autosomal dominant inheritable skeletal disorder characterized by cranial dysplasia, clavicle hypoplasia, and dental abnormalities. Mutations involving Runt-related transcription factor 2 (RUNX2) are currently the only known molecular etiology for CCD but are not identified in all CCD patients. No RUNX2 abnormality can be detected in about 20–30% of patients, and the molecular cause remains unknown. The present study includes a family case with typical features of CCD. RUNX2 mutation was first screened by sequencing analysis, and no mutation was detected. Copy number alterations of the RUNX2 gene were then measured by quantitative PCR and multiplex ligation-dependent probe amplification (MLPA). No copy number variation in RUNX2 could be detected. We performed whole-exome sequencing (WES) to identify the underlying genetic mutations. Unexpectedly, no abnormalities could be detected in genes related to the RUNX2 signaling pathway. Therefore, it was supposed that other new unknown gene variations might contribute to the CCD phenotype. We focused on Immunoglobulin superfamily member 10 (IGSF10), a gene related to bone development. An IGSF10 frameshift mutation (c.6001_6002delCT, p.Leu2001Valfs*24) was detected by WES. Sanger sequencing verified that this mutation was only detected in the patient and her affected mother but not in her unaffected father. Bioinformatics studies demonstrated that this mutation could change the 3D structure of the IGSF10 protein and severely damage its function. In addition, alkaline phosphatase (ALP) activity and the ability to form mineralized nodules were inhibited by IGSF10 knockdown compared with normal controls. The expression of bone sialoprotein (BSP) was significantly reduced by IGSF10 knockdown, but not that of other osteogenic markers. Our results provide new genetic evidence that IGSF10 mutation might contribute to CCD.
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Affiliation(s)
- Dandan Liu
- National Engineering Laboratory for Digital and Material Technology of Stomatology, Department of Preventive Dentistry, National Center of Stomatology, National Clinical Research Center for Oral Diseases, Peking University School and Hospital of Stomatology, Beijing, China
| | - Yang Liu
- National Engineering Laboratory for Digital and Material Technology of Stomatology, Department of Preventive Dentistry, National Center of Stomatology, National Clinical Research Center for Oral Diseases, Peking University School and Hospital of Stomatology, Beijing, China
| | - XianLi Zhang
- National Engineering Laboratory for Digital and Material Technology of Stomatology, Department of Preventive Dentistry, National Center of Stomatology, National Clinical Research Center for Oral Diseases, Peking University School and Hospital of Stomatology, Beijing, China.,Department of Stomatology, Xuanwu Hospital Capital Medical University, Beijing, China
| | - Yixiang Wang
- National Engineering Laboratory for Digital and Material Technology of Stomatology, Central Laboratory, Department of Oral and Maxillofacial Surgery, National Center of Stomatology, National Clinical Research Center for Oral Diseases, Peking University School and Hospital of Stomatology, Beijing, China
| | - Chenying Zhang
- National Engineering Laboratory for Digital and Material Technology of Stomatology, Department of Preventive Dentistry, National Center of Stomatology, National Clinical Research Center for Oral Diseases, Peking University School and Hospital of Stomatology, Beijing, China
| | - Shuguo Zheng
- National Engineering Laboratory for Digital and Material Technology of Stomatology, Department of Preventive Dentistry, National Center of Stomatology, National Clinical Research Center for Oral Diseases, Peking University School and Hospital of Stomatology, Beijing, China
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Manotas MC, González DM, Céspedes C, Forero C, Rojas Moreno AP. Genetic and Epigenetic Control of Puberty. Sex Dev 2021; 16:1-10. [PMID: 34649256 DOI: 10.1159/000519039] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 08/16/2021] [Indexed: 11/19/2022] Open
Abstract
Puberty is a complex transitional phase in which reproductive capacity is achieved. There is a very wide variation in the age range of the onset of puberty, which follows a familial, ethnic, and sex pattern. The hypothalamic-pituitary-gonadal axis and several genetic, environmental, and nutritional factors play an important role in the onset of and throughout puberty. Recently, there has been significant progress in identifying factors that affect normal pubertal timing. Different studies have identified single nucleotide polymorphisms (SNPs) that affect pubertal timing in both sexes and across ethnic groups. Single genes are implicated in both precocious and delayed puberty, and epigenetic mechanisms have been suggested to affect the development and function of the GnRH neuronal network and responsiveness of end organs. All these factors can influence normal puberty timing, precocious puberty, and delayed puberty. The objective of this review is to describe recent findings related to the genetic and epigenetic control of puberty and highlight the need to deepen the knowledge of the regulatory mechanisms of this process in the normal and abnormal context.
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Affiliation(s)
- María Carolina Manotas
- Institute of Human Genetics, Faculty of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Daniel Mauricio González
- Institute of Human Genetics, Faculty of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Camila Céspedes
- Pediatric Endocrinologist, Hospital Universitario San Ignacio, Bogotá, Colombia.,Faculty of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Catalina Forero
- Pediatric Endocrinologist, Hospital Universitario San Ignacio, Bogotá, Colombia.,Faculty of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia
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38
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Saengkaew T, Patel HR, Banerjee K, Butler G, Dattani MT, McGuigan M, Storr HL, Willemsen RH, Dunkel L, Howard SR. Genetic evaluation supports differential diagnosis in adolescent patients with delayed puberty. Eur J Endocrinol 2021; 185:617-627. [PMID: 34403359 PMCID: PMC8558847 DOI: 10.1530/eje-21-0387] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 08/17/2021] [Indexed: 11/08/2022]
Abstract
CONTEXT Pubertal delay can be the clinical presentation of both idiopathic hypogonadotropic hypogonadism (IHH) and self-limited delayed puberty (SLDP). Distinction between these conditions is a common but important diagnostic challenge in adolescents. OBJECTIVE To assess whether gene panel testing can assist with clinical differential diagnosis and to allow accurate and timely management of delayed puberty patients. DESIGN Retrospective study. METHODS Patients presenting with delayed puberty to UK Paediatric services, followed up to final diagnosis, were included. Whole-exome sequencing was analysed using a virtual panel of genes previously reported to cause either IHH or SLDP to identify rarely predicted deleterious variants. Deleterious variants were verified by in silico prediction tools. The correlation between clinical and genotype diagnosis was analysed. RESULTS Forty-six patients were included, 54% with a final clinical diagnosis of SLDP and 46% with IHH. Red flags signs of IHH were present in only three patients. Fifteen predicted deleterious variants in 12 genes were identified in 33% of the cohort, with most inherited in a heterozygous manner. A fair correlation between final clinical diagnosis and genotypic diagnosis was found. Panel testing was able to confirm a diagnosis of IHH in patients with pubertal delay. Genetic analysis identified three patients with IHH that had been previously diagnosed as SLDP. CONCLUSION This study supports the use of targeted exome sequencing in the clinical setting to aid the differential diagnosis between IHH and SLDP in adolescents presenting with pubertal delay. Genetic evaluation thus facilitates earlier and more precise diagnosis, allowing clinicians to direct treatment appropriately.
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Affiliation(s)
- Tansit Saengkaew
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Endocrinology Unit, Department of Paediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Heena R Patel
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Department of Medicine and Health Sciences, Norwich Medical School, University of East Anglia, Norfolk, UK
| | - Kausik Banerjee
- Department of Paediatrics, Barking, Havering and Redbridge University Hospitals NHS Trust, London, UK
| | - Gary Butler
- Department of Paediatric and Adolescent Endocrinology, University College London Hospital NHS Foundation Trust, London, UK
- UCL Great Ormond Street Institute of Child Health, University College London, London, UK
- Correspondence should be addressed to G Butler Email
| | - Mehul T Dattani
- Department of Paediatric and Adolescent Endocrinology, University College London Hospital NHS Foundation Trust, London, UK
- UCL Great Ormond Street Institute of Child Health, University College London, London, UK
- Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Michael McGuigan
- Department of Paediatrics, Countess of Chester NHS Foundation Trust, Chester, UK
| | - Helen L Storr
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Department of Paediatric Endocrinology, Barts Health NHS Trust, London, UK
| | - Ruben H Willemsen
- Department of Paediatric Endocrinology, Barts Health NHS Trust, London, UK
| | - Leo Dunkel
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Department of Paediatric Endocrinology, Barts Health NHS Trust, London, UK
| | - Sasha R Howard
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Department of Paediatric Endocrinology, Barts Health NHS Trust, London, UK
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39
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Nikpour M, Nilsson J, Persson A, Noborn F, Vorontsov E, Larson G. Proteoglycan profiling of human, rat and mouse insulin-secreting cells. Glycobiology 2021; 31:916-930. [PMID: 33997891 PMCID: PMC8434799 DOI: 10.1093/glycob/cwab035] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 03/27/2021] [Accepted: 04/12/2021] [Indexed: 11/30/2022] Open
Abstract
Proteoglycans (PGs) are proteins with glycosaminoglycan (GAG) chains, such as chondroitin sulfate (CS) or heparan sulfate (HS), attached to serine residues. We have earlier shown that prohormones can carry CS, constituting a novel class of PGs. The mapping of GAG modifications of proteins in endocrine cells may thus assist us in delineating possible roles of PGs in endocrine cellular physiology. With this aim, we applied a glycoproteomic approach to identify PGs, their GAG chains and their attachment sites in insulin-secreting cells. Glycopeptides carrying GAG chains were enriched from human pancreatic islets, rat (INS-1 832/13) and mouse (MIN6, NIT-1) insulinoma cell lines by exchange chromatography, depolymerized with GAG lyases, and analyzed by nanoflow liquid chromatography tandem mass spectrometry. We identified CS modifications of chromogranin-A (CgA), islet amyloid polypeptide, secretogranin-1 and secretogranin-2, immunoglobulin superfamily member 10, and protein AMBP. Additionally, we identified two HS-modified prohormones (CgA and secretogranin-1), which was surprising, as prohormones are not typically regarded as HSPGs. For CgA, the glycosylation site carried either CS or HS, making it a so-called hybrid site. Additional HS sites were found on syndecan-1, syndecan-4, nerurexin-2, protein NDNF and testican-1. These results demonstrate that several prohormones, and other constituents of the insulin-secreting cells are PGs. Cell-targeted mapping of the GAG glycoproteome forms an important basis for better understanding of endocrine cellular physiology, and the novel CS and HS sites presented here provide important knowledge for future studies.
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Affiliation(s)
- Mahnaz Nikpour
- Department of Laboratory Medicine, Sahlgrenska Academy, University of Gothenburg, Bruna Stråket 16, SE 413 45 Gothenburg, Sweden
| | - Jonas Nilsson
- Department of Laboratory Medicine, Sahlgrenska Academy, University of Gothenburg, Bruna Stråket 16, SE 413 45 Gothenburg, Sweden
- Proteomics Core Facility, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 9E, SE 405 30 Gothenburg, Sweden
- Laboratory of Clinical Chemistry, Sahlgrenska University Hospital, Bruna Stråket 16, SE 413 45 Gothenburg, Sweden
| | - Andrea Persson
- Department of Laboratory Medicine, Sahlgrenska Academy, University of Gothenburg, Bruna Stråket 16, SE 413 45 Gothenburg, Sweden
| | - Fredrik Noborn
- Department of Laboratory Medicine, Sahlgrenska Academy, University of Gothenburg, Bruna Stråket 16, SE 413 45 Gothenburg, Sweden
| | - Egor Vorontsov
- Proteomics Core Facility, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 9E, SE 405 30 Gothenburg, Sweden
| | - Göran Larson
- Department of Laboratory Medicine, Sahlgrenska Academy, University of Gothenburg, Bruna Stråket 16, SE 413 45 Gothenburg, Sweden
- Proteomics Core Facility, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 9E, SE 405 30 Gothenburg, Sweden
- Laboratory of Clinical Chemistry, Sahlgrenska University Hospital, Bruna Stråket 16, SE 413 45 Gothenburg, Sweden
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40
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Oleari R, Massa V, Cariboni A, Lettieri A. The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency. Int J Mol Sci 2021; 22:9425. [PMID: 34502334 PMCID: PMC8431607 DOI: 10.3390/ijms22179425] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/27/2021] [Accepted: 08/28/2021] [Indexed: 01/19/2023] Open
Abstract
Gonadotropin releasing hormone (GnRH) neurons are hypothalamic neuroendocrine cells that control sexual reproduction. During embryonic development, GnRH neurons migrate from the nose to the hypothalamus, where they receive inputs from several afferent neurons, following the axonal scaffold patterned by nasal nerves. Each step of GnRH neuron development depends on the orchestrated action of several molecules exerting specific biological functions. Mutations in genes encoding for these essential molecules may cause Congenital Hypogonadotropic Hypogonadism (CHH), a rare disorder characterized by GnRH deficiency, delayed puberty and infertility. Depending on their action in the GnRH neuronal system, CHH causative genes can be divided into neurodevelopmental and neuroendocrine genes. The CHH genetic complexity, combined with multiple inheritance patterns, results in an extreme phenotypic variability of CHH patients. In this review, we aim at providing a comprehensive and updated description of the genes thus far associated with CHH, by dissecting their biological relevance in the GnRH system and their functional relevance underlying CHH pathogenesis.
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Affiliation(s)
- Roberto Oleari
- Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milano, Italy;
| | - Valentina Massa
- Department of Health Sciences, University of Milan, 20142 Milano, Italy;
- CRC Aldo Ravelli for Neurotechnology and Experimental Brain Therapeutics, Department of Health Sciences, University of Milan, 20142 Milano, Italy
| | - Anna Cariboni
- Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milano, Italy;
| | - Antonella Lettieri
- Department of Health Sciences, University of Milan, 20142 Milano, Italy;
- CRC Aldo Ravelli for Neurotechnology and Experimental Brain Therapeutics, Department of Health Sciences, University of Milan, 20142 Milano, Italy
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41
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Louden ED, Poch A, Kim HG, Ben-Mahmoud A, Kim SH, Layman LC. Genetics of hypogonadotropic Hypogonadism-Human and mouse genes, inheritance, oligogenicity, and genetic counseling. Mol Cell Endocrinol 2021; 534:111334. [PMID: 34062169 DOI: 10.1016/j.mce.2021.111334] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 05/12/2021] [Accepted: 05/24/2021] [Indexed: 12/14/2022]
Abstract
Hypogonadotropic hypogonadism, which may be normosmic (nHH) or anosmic/hyposmic, known as Kallmann syndrome (KS), is due to gonadotropin-releasing hormone deficiency, which results in absent puberty and infertility. Investigation of the genetic basis of nHH/KS over the past 35 years has yielded a substantial increase in our understanding, as variants in 44 genes in OMIM account for ~50% of cases. The first genes for KS (ANOS1) and nHH (GNRHR) were followed by the discovery that FGFR1 variants may cause either nHH or KS. Associated anomalies include midline facial defects, neurologic deficits, cardiac anomalies, and renal agenesis, among others. Mouse models for all but one gene (ANOS1) generally support findings in humans. About half of the known genes implicated in nHH/KS are inherited as autosomal dominant and half are autosomal recessive, whereas only 7% are X-linked recessive. Digenic and oligogenic inheritance has been reported in 2-20% of patients, most commonly with variants in genes that may result in either nHH or KS inherited in an autosomal dominant fashion. In vitro analyses have only been conducted for both gene variants in eight cases and for one gene variant in 20 cases. Rigorous confirmation that two gene variants in the same individual cause the nHH/KS phenotype is lacking for most. Clinical diagnosis is probably best accomplished by targeted next generation sequencing of the known candidate genes with confirmation by Sanger sequencing. Elucidation of the genetic basis of nHH/KS has resulted in an enhanced understanding of this disorder, as well as normal puberty, which makes genetic diagnosis clinically relevant.
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Affiliation(s)
- Erica D Louden
- Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Department of Neuroscience & Regenerative Medicine, Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA
| | - Alexandra Poch
- Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Department of Neuroscience & Regenerative Medicine, Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA
| | - Hyung-Goo Kim
- Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar
| | - Afif Ben-Mahmoud
- Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar
| | - Soo-Hyun Kim
- Molecular and Clinical Sciences Research Institute, St. George's, University of London, Cranmer Terrace, London, SW17 0RE, United Kingdom
| | - Lawrence C Layman
- Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Department of Neuroscience & Regenerative Medicine, Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA.
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42
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Davis EE, Balasubramanian R, Kupchinsky ZA, Keefe DL, Plummer L, Khan K, Meczekalski B, Heath KE, Lopez-Gonzalez V, Ballesta-Martinez MJ, Margabanthu G, Price S, Greening J, Brauner R, Valenzuela I, Cusco I, Fernandez-Alvarez P, Wierman ME, Li T, Lage K, Barroso PS, Chan YM, Crowley WF, Katsanis N. TCF12 haploinsufficiency causes autosomal dominant Kallmann syndrome and reveals network-level interactions between causal loci. Hum Mol Genet 2021; 29:2435-2450. [PMID: 32620954 DOI: 10.1093/hmg/ddaa120] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 05/27/2020] [Accepted: 06/11/2020] [Indexed: 12/12/2022] Open
Abstract
Dysfunction of the gonadotropin-releasing hormone (GnRH) axis causes a range of reproductive phenotypes resulting from defects in the specification, migration and/or function of GnRH neurons. To identify additional molecular components of this system, we initiated a systematic genetic interrogation of families with isolated GnRH deficiency (IGD). Here, we report 13 families (12 autosomal dominant and one autosomal recessive) with an anosmic form of IGD (Kallmann syndrome) with loss-of-function mutations in TCF12, a locus also known to cause syndromic and non-syndromic craniosynostosis. We show that loss of tcf12 in zebrafish larvae perturbs GnRH neuronal patterning with concomitant attenuation of the orthologous expression of tcf3a/b, encoding a binding partner of TCF12, and stub1, a gene that is both mutated in other syndromic forms of IGD and maps to a TCF12 affinity network. Finally, we report that restored STUB1 mRNA rescues loss of tcf12 in vivo. Our data extend the mutational landscape of IGD, highlight the genetic links between craniofacial patterning and GnRH dysfunction and begin to assemble the functional network that regulates the development of the GnRH axis.
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Affiliation(s)
- Erica E Davis
- Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA.,Advanced Center for Translational and Genetic Medicine (ACT-GeM), Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.,Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Ravikumar Balasubramanian
- Harvard Reproductive Endocrine Science Center, Massachusetts General Hospital (MGH), Boston, MA 02114, USA.,Harvard Medical School, Boston, MA 02115, USA
| | | | - David L Keefe
- Harvard Reproductive Endocrine Science Center, Massachusetts General Hospital (MGH), Boston, MA 02114, USA
| | - Lacey Plummer
- Harvard Reproductive Endocrine Science Center, Massachusetts General Hospital (MGH), Boston, MA 02114, USA
| | - Kamal Khan
- Advanced Center for Translational and Genetic Medicine (ACT-GeM), Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.,Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Blazej Meczekalski
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, 60-512 Poznan, Poland
| | - Karen E Heath
- Institute of Medical and Molecular Genetics (INGEMM) Hospital Universitario La Paz, Universidad Autonoma de Madrid, IdiPAZ, Madrid, Spain and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, 28046 Madrid, Spain
| | - Vanesa Lopez-Gonzalez
- Medical Genetics Unit, Department of Pediatrics, Hospital Clinico, Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain and CIBERER, ISCIII, 28046 Madrid, Spain
| | - Mary J Ballesta-Martinez
- Medical Genetics Unit, Department of Pediatrics, Hospital Clinico, Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain and CIBERER, ISCIII, 28046 Madrid, Spain
| | | | - Susan Price
- Northampton General Hospital, Northampton NN1 5BD, UK
| | - James Greening
- University Hospitals of Leicester, Leicester LE3 9QP, UK
| | - Raja Brauner
- Pediatric Endocrinology Unit, Fondation Ophtalmologique Adolphe de Rothschild and Université Paris Descartes, 75019 Paris, France
| | - Irene Valenzuela
- Department of Clinical and Molecular Genetics, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.,Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Ivon Cusco
- Department of Clinical and Molecular Genetics, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.,Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Paula Fernandez-Alvarez
- Department of Clinical and Molecular Genetics, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.,Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Margaret E Wierman
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Taibo Li
- Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.,Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.,Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Kasper Lage
- Harvard Medical School, Boston, MA 02115, USA.,Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.,Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Priscila Sales Barroso
- Divisao de Endocrinologia e Metabologia, Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, 05403-900 Brazil
| | - Yee-Ming Chan
- Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA
| | - William F Crowley
- Harvard Medical School, Boston, MA 02115, USA.,MGH Center for Human Genetics & The Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston MA 02114, USA
| | - Nicholas Katsanis
- Center for Human Disease Modeling, Duke University, Durham, NC 27701, USA.,Advanced Center for Translational and Genetic Medicine (ACT-GeM), Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.,Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
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Jonsdottir-Lewis E, Feld A, Ciarlo R, Denhoff E, Feldman HA, Chan YM. Timing of Pubertal Onset in Girls and Boys With Constitutional Delay. J Clin Endocrinol Metab 2021; 106:e3693-e3703. [PMID: 33890108 PMCID: PMC8372671 DOI: 10.1210/clinem/dgab270] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Indexed: 12/17/2022]
Abstract
CONTEXT The decision whether to treat a child with delayed puberty with sex steroids is primarily based on patient, family, and provider preference. Knowing when children with constitutional delay eventually enter puberty would inform this decision. OBJECTIVE, DESIGN, SETTING, PARTICIPANTS, AND OUTCOME MEASURES To estimate and compare rates of pubertal entry, we conducted a retrospective cohort study by reviewing medical records of children evaluated for delayed puberty at a large academic medical center between 2000 and 2015, extracting data on pubertal status for all clinical visits, then conducting time-to-event analyses. RESULTS Of 392 girls and 683 boys with delayed puberty, constitutional delay was the most common cause, found in 32% of girls and 70% of boys. In a subcohort of 97 girls and 243 boys who were prepubertal at one or more visits, we observed a broad age range for pubertal entry, up to >16 years for girls and >17 years for boys. The probability of entering puberty within the next year for 12- to 15.5-year-old girls and 13.5- to 16.5-year-old boys with delayed puberty ranged between 38% and 74%. No differences in the rates of pubertal entry were seen between girls and boys after data harmonization. CONCLUSION The broad range of ages at pubertal entry for children with constitutional delay challenges the concept that constitutional delay is merely an extreme of normal variation. Discussions with patients and families about management should consider the possibility that some children may need to wait years after presentation until puberty starts.
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Affiliation(s)
- Elfa Jonsdottir-Lewis
- Division of Endocrinology, Department of Pediatrics, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Amalia Feld
- Division of Endocrinology, Department of Pediatrics, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Ryan Ciarlo
- Division of Endocrinology, Department of Pediatrics, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Erica Denhoff
- Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Henry A Feldman
- Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital, Boston, MA 02115, USA
| | - Yee-Ming Chan
- Division of Endocrinology, Department of Pediatrics, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
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44
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Ling B, Liao X, Tang Q, Ye G, Bin X, Wang J, Pang Y, Qi G. MicroRNA-106b-5p inhibits growth and progression of lung adenocarcinoma cells by downregulating IGSF10. Aging (Albany NY) 2021; 13:18740-18756. [PMID: 34351868 PMCID: PMC8351668 DOI: 10.18632/aging.203318] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 05/18/2021] [Indexed: 12/04/2022]
Abstract
In this study, we investigated the mechanistic role and prognostic significance of IGSF10 in lung adenocarcinoma. Oncomine database analysis showed that IGSF10 expression was significantly reduced in most cancer types, including lung adenocarcinoma (LUAD). In the TCGA-LUAD dataset, IGSF10 expression correlated positively with proportions of tumor-infiltrated B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells. Kaplan-Meier survival analysis showed that overall survival of patients with low IGSF10 expression was significantly shorter than those with high IGSF10 expression. MiRWalk2.0 database analysis and dual luciferase reporter assays confirmed that miR-106b-5p suppressed IGSF10 expression by binding to its 3’UTR. MiR-106b-5p levels inversely correlated with IGSF10 expression in the TCGA-LUAD dataset. Moreover, inhibition of miR-106b-5p significantly decreased in vitro proliferation, migration, and invasion by LUAD cells, whereas miR-106b-5p overexpression reversed those effects. These results demonstrate that IGSF10 is an independent prognostic factor for LUAD. Furthermore, miR-106b-5p suppressed IGSF10 expression in LUAD tissues by binding to its 3’UTR, which makes IGSF10 and miR-106b-5p potential prognostic biomarkers and therapeutic targets in LUAD patients.
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Affiliation(s)
- Bo Ling
- College of Pharmacy, Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China
| | - Xianjiu Liao
- College of Pharmacy, Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China
| | - Qiang Tang
- Department of Burn and Plastic Surgery and Wound Repair, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China
| | - Guangbin Ye
- College of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China.,Medical College of Guangxi University, Nanning 530004, Guangxi, China
| | - Xiaoyun Bin
- College of Basic Medical Sciences, Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China
| | - Jianchu Wang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China
| | - Yaqin Pang
- College of Medical Laboratory, Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China
| | - Guangzi Qi
- College of Public Health and Management, Youjiang Medical University for Nationalities, Baise 533000, Guangxi, China
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45
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Gupta M, Liu X, Teraoka SN, Wright JA, Gatti RA, Quinlan A, Concannon P. Genes affecting ionizing radiation survival identified through combined exome sequencing and functional screening. Hum Mutat 2021; 42:1124-1138. [PMID: 34153142 DOI: 10.1002/humu.24241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 05/04/2021] [Accepted: 06/13/2021] [Indexed: 11/09/2022]
Abstract
The study of genetic syndromes characterized by sensitivity to DNA damaging agents has provided important insights into the mechanisms that maintain genome stability and identified novel targets for cancer therapies. Here, we used exome sequencing to study 51 unrelated individuals with previously reported hypersensitivity to ionizing radiation as well as a range of neurologic, immunologic, and developmental features, but who did not clearly fit any previously defined genetic syndrome. Based on the combination of variant identification, computational evidence of deleteriousness, and functional screening, we identified three groups of subjects. Two subjects carried the bi-allelic loss of function variants in causative genes for known DNA damage response syndromes. Eight subjects carried the single loss of function variants in causative genes for DNA damage response syndromes, six of whom also carried predicted deleterious variants in other genes with DNA damage-related functions. Three subjects carried deleterious mutations in genes without obvious roles in DNA damage responses. However, treatment of U2OS cells with small interfering RNA targeting these genes resulted in significantly increased radiation sensitivity. Our results suggest that gene-gene interaction may contribute to ionizing radiation sensitivity as well as highlighting possible roles for several genes not obviously involved in the response to DNA damage.
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Affiliation(s)
- Meenal Gupta
- Department of Human Genetics and Department of Biomedical Informatics, University of Utah, Salt Lake City, Utah, USA
| | - Xiangfei Liu
- Genetics Institute and Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, USA
| | - Sharon N Teraoka
- Genetics Institute and Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, USA
| | - Jocyndra A Wright
- Genetics Institute and Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, USA
| | - Richard A Gatti
- UCLA Department of Pathology and Laboratory Medicine, and Department of Human Genetics, Los Angeles, California, USA
| | - Aaron Quinlan
- Department of Human Genetics and Department of Biomedical Informatics, University of Utah, Salt Lake City, Utah, USA
| | - Patrick Concannon
- Genetics Institute and Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, USA
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46
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Defects in GnRH Neuron Migration/Development and Hypothalamic-Pituitary Signaling Impact Clinical Variability of Kallmann Syndrome. Genes (Basel) 2021; 12:genes12060868. [PMID: 34198905 PMCID: PMC8229512 DOI: 10.3390/genes12060868] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 05/30/2021] [Accepted: 06/03/2021] [Indexed: 11/16/2022] Open
Abstract
Kallmann syndrome (KS) is a combination of isolated hypogonadotropic hypogonadism (IHH) with olfactory dysfunction, representing a heterogeneous disorder with a broad phenotypic spectrum. The genetic background of KS has not yet been fully established. This study was conducted on 46 Polish KS subjects (41 males, 5 females; average age: 29 years old). The studied KS patients were screened for defects in a 38-gene panel with next-generation sequencing (NGS) technology. The analysis revealed 27 pathogenic and likely pathogenic (P/LP) variants, and 21 variants of uncertain significance (VUS). The P/LP variants were detected in 20 patients (43.5%). The prevalence of oligogenic P/LP defects in selected genes among KS patients was 26% (12/46), whereas the co-occurrence of other variants was detected in 43% (20 probands). The examined KS patients showed substantial genotypic and phenotypic variability. A marked difference in non-reproductive phenotypes, involving defects in genes responsible for GnRH neuron development/migration and genes contributing to pituitary development and signaling, was observed. A comprehensive gene panel for IHH testing enabled the detection of clinically relevant variants in the majority of KS patients, which makes targeted NGS an effective molecular tool. The significance of oligogenicity and the high incidence of alterations in selected genes should be further elucidated.
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Vanacker C, Bouret SG, Giacobini P, Prévot V. [Precocious puberty and neuropilin-1 signaling in GnRH neurons]. Med Sci (Paris) 2021; 37:366-371. [PMID: 33908854 DOI: 10.1051/medsci/2021035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
The survival of the species depends on two closely interlinked processes: the correct functioning of the reproductive system, and the balance between the energy needs of an individual and the supply of energy sources through feeding. These two processes are regulated in the hypothalamus, which produces neurohormones that control various physiological functions. Among these neurohormones, GnRH controls not only the maturation and function of the reproductive organs, including the ovaries and the testes, during puberty and in adulthood, but also sexual attraction. Recent evidence suggest that neuropilin-1-mediated signaling in GnRH-synthesizing neurons could be a linchpin that holds together various neuroanatomical, physiological and behavioral adaptations involved in triggering puberty and achieving reproductive function.
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Affiliation(s)
- Charlotte Vanacker
- Univ. Lille, Inserm, CHU Lille, Équipe développement et plasticité du cerveau neuroendocrine, FHU 1 000 jours pour la Santé, Lille Neuroscience et Cognition, UMR-S1172, 1 place de Verdun, 59045 Lille Cedex, France
| | - Sébastien G Bouret
- Univ. Lille, Inserm, CHU Lille, Équipe développement et plasticité du cerveau neuroendocrine, FHU 1 000 jours pour la Santé, Lille Neuroscience et Cognition, UMR-S1172, 1 place de Verdun, 59045 Lille Cedex, France
| | - Paolo Giacobini
- Univ. Lille, Inserm, CHU Lille, Équipe développement et plasticité du cerveau neuroendocrine, FHU 1 000 jours pour la Santé, Lille Neuroscience et Cognition, UMR-S1172, 1 place de Verdun, 59045 Lille Cedex, France
| | - Vincent Prévot
- Univ. Lille, Inserm, CHU Lille, Équipe développement et plasticité du cerveau neuroendocrine, FHU 1 000 jours pour la Santé, Lille Neuroscience et Cognition, UMR-S1172, 1 place de Verdun, 59045 Lille Cedex, France
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48
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Wojtowicz WM, Vielmetter J, Fernandes RA, Siepe DH, Eastman CL, Chisholm GB, Cox S, Klock H, Anderson PW, Rue SM, Miller JJ, Glaser SM, Bragstad ML, Vance J, Lam AW, Lesley SA, Zinn K, Garcia KC. A Human IgSF Cell-Surface Interactome Reveals a Complex Network of Protein-Protein Interactions. Cell 2021; 182:1027-1043.e17. [PMID: 32822567 PMCID: PMC7440162 DOI: 10.1016/j.cell.2020.07.025] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 05/19/2020] [Accepted: 07/17/2020] [Indexed: 12/17/2022]
Abstract
Cell-surface protein-protein interactions (PPIs) mediate cell-cell communication, recognition, and responses. We executed an interactome screen of 564 human cell-surface and secreted proteins, most of which are immunoglobulin superfamily (IgSF) proteins, using a high-throughput, automated ELISA-based screening platform employing a pooled-protein strategy to test all 318,096 PPI combinations. Screen results, augmented by phylogenetic homology analysis, revealed ∼380 previously unreported PPIs. We validated a subset using surface plasmon resonance and cell binding assays. Observed PPIs reveal a large and complex network of interactions both within and across biological systems. We identified new PPIs for receptors with well-characterized ligands and binding partners for “orphan” receptors. New PPIs include proteins expressed on multiple cell types and involved in diverse processes including immune and nervous system development and function, differentiation/proliferation, metabolism, vascularization, and reproduction. These PPIs provide a resource for further biological investigation into their functional relevance and may offer new therapeutic drug targets.
Human IgSF interactome reveals complex network of cell-surface protein interactions Phylogenetic homology analysis predicts protein-protein interactions ∼380 previously unknown protein-protein interactions identified Deorphanization of receptors and new binding partners for well-studied receptors
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Affiliation(s)
- Woj M Wojtowicz
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
| | - Jost Vielmetter
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - Ricardo A Fernandes
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Dirk H Siepe
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Catharine L Eastman
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Gregory B Chisholm
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - Sarah Cox
- The Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA
| | - Heath Klock
- The Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA
| | - Paul W Anderson
- The Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA
| | - Sarah M Rue
- The Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA
| | - Jessica J Miller
- The Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA
| | - Scott M Glaser
- The Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA
| | - Melisa L Bragstad
- The Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA
| | - Julie Vance
- The Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA
| | - Annie W Lam
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - Scott A Lesley
- The Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA
| | - Kai Zinn
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - K Christopher Garcia
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
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49
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Delaney A, Burkholder AB, Lavender CA, Plummer L, Mericq V, Merino PM, Quinton R, Lewis KL, Meader BN, Albano A, Shaw ND, Welt CK, Martin KA, Seminara SB, Biesecker LG, Bailey-Wilson JE, Hall JE. Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women With Hypothalamic Amenorrhea. J Clin Endocrinol Metab 2021; 106:e1441-e1452. [PMID: 32870266 PMCID: PMC7947783 DOI: 10.1210/clinem/dgaa609] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 08/28/2020] [Indexed: 12/17/2022]
Abstract
CONTEXT Functional hypothalamic amenorrhea (HA) is a common, acquired form of hypogonadotropic hypogonadism that occurs in the setting of energy deficits and/or stress. Variability in individual susceptibility to these stressors, HA heritability, and previous identification of several rare sequence variants (RSVs) in genes associated with the rare disorder, isolated hypogonadotropic hypogonadism (IHH), in individuals with HA suggest a possible genetic contribution to HA susceptibility. OBJECTIVE We sought to determine whether the burden of RSVs in IHH-related genes is greater in women with HA than controls. DESIGN We compared patients with HA to control women. SETTING The study was conducted at secondary referral centers. PATIENTS AND OTHER PARTICIPANTS Women with HA (n = 106) and control women (ClinSeq study; n = 468). INTERVENTIONS We performed exome sequencing in all patients and controls. MAIN OUTCOME MEASURE(S) The frequency of RSVs in 53 IHH-associated genes was determined using rare variant burden and association tests. RESULTS RSVs were overrepresented in women with HA compared with controls (P = .007). Seventy-eight heterozygous RSVs in 33 genes were identified in 58 women with HA (36.8% of alleles) compared to 255 RSVs in 41 genes among 200 control women (27.2%). CONCLUSIONS Women with HA are enriched for RSVs in genes that cause IHH, suggesting that variation in genes associated with gonadotropin-releasing hormone neuronal ontogeny and function may be a major determinant of individual susceptibility to developing HA in the face of diet, exercise, and/or stress.
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Affiliation(s)
- Angela Delaney
- National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, North Carolina
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland
| | - Adam B Burkholder
- National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, North Carolina
| | - Christopher A Lavender
- National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, North Carolina
| | - Lacey Plummer
- Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Veronica Mericq
- Institute of Maternal and Child Research, University of Chile, Santiago, Chile
- Department of Pediatrics, Clínica Las Condes, Santiago, Chile
| | - Paulina M Merino
- Institute of Maternal and Child Research, University of Chile, Santiago, Chile
| | - Richard Quinton
- Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK
| | - Katie L Lewis
- Medical Genomics & Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland
| | - Brooke N Meader
- National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, North Carolina
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland
| | - Alessandro Albano
- National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, North Carolina
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland
| | - Natalie D Shaw
- National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, North Carolina
| | - Corrine K Welt
- Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, Utah
| | - Kathryn A Martin
- Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Stephanie B Seminara
- Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Leslie G Biesecker
- Medical Genomics & Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland
| | - Joan E Bailey-Wilson
- Computational and Statistical Genomics Branch, National Human Genome Research Institute, NIH, Baltimore, Maryland
| | - Janet E Hall
- National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, North Carolina
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50
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Persani L, Bonomi M, Cools M, Dattani M, Dunkel L, Gravholt CH, Juul A. ENDO-ERN expert opinion on the differential diagnosis of pubertal delay. Endocrine 2021; 71:681-688. [PMID: 33512657 PMCID: PMC8016789 DOI: 10.1007/s12020-021-02626-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 01/09/2021] [Indexed: 12/15/2022]
Abstract
The differential diagnoses of pubertal delay include hypergonadotropic hypogonadism and congenital hypogonadotropic hypogonadism (CHH), as well as constitutional delay of growth and puberty (CDGP). Distinguishing between CDGP and CHH may be challenging, and the scientific community has been struggling to develop diagnostic tests that allow an accurate differential diagnosis. Indeed, an adequate and timely management is critical in order to enable optimal clinical and psychosocial outcomes of the different forms of pubertal delays. In this review, we provide an updated insight on the differential diagnoses of pubertal delay, including the available tests, their meanings and accuracy, as well as some clues to effectively orientate towards either constitutional pubertal delay or pathologic CHH and hypergonadotropic hypogonadism.
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Affiliation(s)
- Luca Persani
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.
| | - Marco Bonomi
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Martine Cools
- Department of Internal Medicine and Pediatrics, Ghent University and Pediatric Endocrinology Service, Ghent University Hospital, Ghent, Belgium
| | - Mehul Dattani
- Genetics and Genomic Medicine Research and Teaching Programme, UCL GOS Institute of Child Health, London, UK
- Department of Endocrinology, Great Ormond Street Hospital for Children, London, UK
| | - Leo Dunkel
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ, London, UK
| | - Claus H Gravholt
- Department of Endocrinology, Aarhus University Hospital, Aarhus, Denmark
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Anders Juul
- Department of Growth and Reproduction, University of Copenhagen, Rigshospitalet, Denmark
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