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Wang Q, Liu M, Cao BY, Su C, Meng X, Ding Y, Ren XY, Gong CX. Osteoporosis Caused by Monoallelic Variant of WNT1 Gene in Four Pediatric Patients. Am J Med Genet A 2025; 197:e63987. [PMID: 39780405 DOI: 10.1002/ajmg.a.63987] [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: 08/29/2024] [Revised: 12/28/2024] [Accepted: 12/30/2024] [Indexed: 01/11/2025]
Abstract
Pediatric patients of autosomal dominant early onset osteoporosis conferred by heterozygous mutation in the WNT1 (OMIM: 615221) were rarely reported, and therapy in pediatrics is relatively inexperienced. The clinical and genotypic characteristics and treatment process of four children with osteoporosis caused by WNT1 monoallelic variation were analyzed. The patients admitted from June 2023 to January 2024. All patients presented multiple vertebral compression fracture, two of them experienced recurrent peripheral fragility fractures. The age of the first fractures occur between 2 years and 12 years. Lumber BMD by dual-energy X-ray absorptiometry were decreased (height adjusted z score of -8.06 to -3.50). Four monoallelic variants in WNT1 (c.505G>T, c.616G>A, c.677C>T and c. 506G>A with transcript ID. NM_005430.4) were identified in the probands, and relatives carrying mutations presented with a bone phenotype, consistent with autosomal dominant inheritance. Novel variant c.616G>A was analyzed by 3D protein structural modeling. Subsequent to the treatment of zelodronic acid on all four patients, lumbar BMD improvement by 0.061-0.251 g/cm2. Our data showed that the age of onset of osteoporosis by monoallelic variants in WNT1 is significantly earlier than the age of onset in the general population. Severe osteoporosis is also exhibited in pediatric patients, not just in aging patients with WNT1 variant. Zoledronic acid treatment is effective in short-term observation for pediatric patients with improvement of bone pain and BMD, and no more facture during treatment.
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Affiliation(s)
- Qiao Wang
- Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Min Liu
- Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Bing-Yan Cao
- Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Chang Su
- Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Xi Meng
- Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Yuan Ding
- Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Xiao-Ya Ren
- Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Chun-Xiu Gong
- Department of Endocrinology, Genetics and Metabolism, Beijing Children's Hospital, Capital Medical University, Beijing, China
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Jovanovic M, Marini JC. Update on the Genetics of Osteogenesis Imperfecta. Calcif Tissue Int 2024; 115:891-914. [PMID: 39127989 PMCID: PMC11607015 DOI: 10.1007/s00223-024-01266-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 07/22/2024] [Indexed: 08/12/2024]
Abstract
Osteogenesis imperfecta (OI) is a heterogeneous heritable skeletal dysplasia characterized by bone fragility and deformity, growth deficiency, and other secondary connective tissue defects. OI is now understood as a collagen-related disorder caused by defects of genes whose protein products interact with collagen for folding, post-translational modification, processing and trafficking, affecting bone mineralization and osteoblast differentiation. This review provides the latest updates on genetics of OI, including new developments in both dominant and rare OI forms, as well as the signaling pathways involved in OI pathophysiology. There is a special emphasis on discoveries of recessive mutations in TENT5A, MESD, KDELR2 and CCDC134 whose causality of OI types XIX, XX, XXI and XXI, respectively, is now established and expends the complexity of mechanisms underlying OI to overlap LRP5/6 and MAPK/ERK pathways. We also review in detail new discoveries connecting the known OI types to each other, which may underlie an eventual understanding of a final common pathway in OI cellular and bone biology.
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Affiliation(s)
- Milena Jovanovic
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
- Section on Adolescent Bone and Body Composition, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Joan C Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
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Mehta P, Vishvkarma R, Gupta S, Chattopadhyay N, Rajender S. Exome sequencing identified mutations in the WNT1 and COL1A2 genes in osteogenesis imperfecta cases. Mol Biol Rep 2024; 51:449. [PMID: 38536562 DOI: 10.1007/s11033-024-09326-7] [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: 10/22/2023] [Accepted: 02/07/2024] [Indexed: 04/11/2024]
Abstract
BACKGROUND Osteogenesis imperfecta (OI) is a heritable connective tissue disorder characterized by bone deformities, fractures and reduced bone mass. OI can be inherited as a dominant, recessive, or X-linked disorder. The mutational spectrum has shown that autosomal dominant mutations in the type I collagen-encoding genes are responsible for OI in 85% of the cases. Apart from collagen genes, mutations in more than 20 other genes, such as CRTAP, CREB3L1, MBTPS2, P4HB, SEC24D, SPARC, FKBP10, LEPRE1, PLOD2, PPIB, SERPINF1, SERPINH1, SP7, WNT1, BMP1, TMEM38B, and IFITM5 have been reported in OI. METHODS AND RESULTS To understand the genetic cause of OI in four cases, we conducted whole exome sequencing, followed by Sanger sequencing. In case #1, we identified a novel c.506delG homozygous mutation in the WNT1 gene, resulting in a frameshift and early truncation of the protein at the 197th amino acid. In cases #2, 3 and 4, we identified a heterozygous c.838G > A mutation in the COL1A2 gene, resulting in a p.Gly280Ser substitution. The clinvar frequency of this mutation is 0.000008 (GnomAD-exomes). This mutation has been identified by other studies as well and appears to be a mutational hot spot. These pathogenic mutations were found to be absent in 96 control samples analyzed for these sites. The presence of these mutations in the cases, their absence in controls, their absence or very low frequency in general population, and their evaluation using various in silico prediction tools suggested their pathogenic nature. CONCLUSIONS Mutations in the WNT1 and COL1A2 genes explain these cases of osteogenesis imperfecta.
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Affiliation(s)
- Poonam Mehta
- Division of Endocrinology and Centre for ASTHI, CSIR-Central Drug Research Institute, Lucknow, 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Rahul Vishvkarma
- Division of Endocrinology and Centre for ASTHI, CSIR-Central Drug Research Institute, Lucknow, 226031, India
| | - Sushil Gupta
- Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Naibedya Chattopadhyay
- Division of Endocrinology and Centre for ASTHI, CSIR-Central Drug Research Institute, Lucknow, 226031, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Singh Rajender
- Division of Endocrinology and Centre for ASTHI, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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Formosa MM, Christou MA, Mäkitie O. Bone fragility and osteoporosis in children and young adults. J Endocrinol Invest 2024; 47:285-298. [PMID: 37668887 PMCID: PMC10859323 DOI: 10.1007/s40618-023-02179-0] [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: 07/05/2023] [Accepted: 08/16/2023] [Indexed: 09/06/2023]
Abstract
Osteoporosis is a metabolic bone disorder which increases fragility fracture risk. Elderly individuals, especially postmenopausal women, are particularly susceptible to osteoporosis. Although rare, osteoporosis in children and young adults is becoming increasingly evident, highlighting the need for timely diagnosis, management and follow-up. Early-onset osteoporosis is defined as the presence of a low BMD (Z-score of ≤ -2.0 in individuals aged < 20 years; T-score of ≤ -2.5 in those aged between 20 to 50 years) accompanied by a clinically significant fracture history, or the presence of low-energy vertebral compression fractures even in the absence of osteoporosis. Affected children and young adults should undergo a thorough diagnostic workup, including collection of clinical history, radiography, biochemical investigation and possibly bone biopsy. Once secondary factors and comorbidities are excluded, genetic testing should be considered to determine the possibility of an underlying monogenic cause. Defects in genes related to type I collagen biosynthesis are the commonest contributors of primary osteoporosis, followed by loss-of-function variants in genes encoding key regulatory proteins of canonical WNT signalling (specifically LRP5 and WNT1), the actin-binding plastin-3 protein (encoded by PLS3) resulting in X-linked osteoporosis, and the more recent sphingomyelin synthase 2 (encoded by SGMS2) which is critical for signal transduction affecting sphingomyelin metabolism. Despite these discoveries, genetic causes and underlying mechanisms in early-onset osteoporosis remain largely unknown, and if no causal gene is identified, early-onset osteoporosis is deemed idiopathic. This calls for further research to unravel the molecular mechanisms driving early-onset osteoporosis that consequently will aid in patient management and individualised targeted therapy.
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Affiliation(s)
- M M Formosa
- Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, Malta
- Center for Molecular Medicine and Biobanking, University of Malta, Msida, Malta
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - M A Christou
- Department of Endocrinology, School of Medicine, University of Ioannina, Ioannina, Greece
- Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, Ioannina, Greece
| | - O Mäkitie
- Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- Folkhälsan Research Centre, Folkhälsan Institute of Genetics, Helsinki, Finland.
- Department of Molecular Medicine and Surgery, Karolinska Institutet, and Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
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Sun Y, Li L, Wang J, Liu H, Wang H. Emerging Landscape of Osteogenesis Imperfecta Pathogenesis and Therapeutic Approaches. ACS Pharmacol Transl Sci 2024; 7:72-96. [PMID: 38230285 PMCID: PMC10789133 DOI: 10.1021/acsptsci.3c00324] [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: 11/12/2023] [Revised: 12/10/2023] [Accepted: 12/12/2023] [Indexed: 01/18/2024]
Abstract
Osteogenesis imperfecta (OI) is an uncommon genetic disorder characterized by shortness of stature, hearing loss, poor bone mass, recurrent fractures, and skeletal abnormalities. Pathogenic variations have been found in over 20 distinct genes that are involved in the pathophysiology of OI, contributing to the disorder's clinical and genetic variability. Although medications, surgical procedures, and other interventions can partially alleviate certain symptoms, there is still no known cure for OI. In this Review, we provide a comprehensive overview of genetic pathogenesis, existing treatment modalities, and new developments in biotechnologies such as gene editing, stem cell reprogramming, functional differentiation, and transplantation for potential future OI therapy.
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Affiliation(s)
- Yu Sun
- PET
Center, Chongqing University Three Gorges
Hospital, Chongqing 404000, China
| | - Lin Li
- PET
Center, Chongqing University Three Gorges
Hospital, Chongqing 404000, China
| | - Jiajun Wang
- Medical
School of Hubei Minzu University, Enshi 445000, China
| | - Huiting Liu
- PET
Center, Chongqing University Three Gorges
Hospital, Chongqing 404000, China
| | - Hu Wang
- Department
of Neurology, Johns Hopkins University School
of Medicine, Baltimore, Maryland 21205, United States
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Yu H, Li C, Wu H, Xia W, Wang Y, Zhao J, Xu C. Pathogenic mechanisms of osteogenesis imperfecta, evidence for classification. Orphanet J Rare Dis 2023; 18:234. [PMID: 37559063 PMCID: PMC10411007 DOI: 10.1186/s13023-023-02849-5] [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: 07/31/2023] [Indexed: 08/11/2023] Open
Abstract
Osteogenesis imperfecta (OI) is a connective tissue disorder affecting the skeleton and other organs, which has multiple genetic patterns, numerous causative genes, and complex pathogenic mechanisms. The previous classifications lack structure and scientific basis and have poor applicability. In this paper, we summarize and sort out the pathogenic mechanisms of OI, and analyze the molecular pathogenic mechanisms of OI from the perspectives of type I collagen defects(synthesis defects, processing defects, post-translational modification defects, folding and cross-linking defects), bone mineralization disorders, osteoblast differentiation and functional defects respectively, and also generalize several new untyped OI-causing genes and their pathogenic mechanisms, intending to provide the evidence of classification and a scientific basis for the precise diagnosis and treatment of OI.
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Affiliation(s)
- Hongjie Yu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
| | - Changrong Li
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
| | - Huixiao Wu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
| | - Weibo Xia
- Department of Endocrinology, Key Laboratory of Endocrinology, Peking Union Medical College Hospital, National Commission of Health, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, 100730
| | - Yanzhou Wang
- Department of Pediatric Orthopedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Jiajun Zhao
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
| | - Chao Xu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China.
- Shandong Engineering Research Center of Stem Cell and Gene Therapy for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China.
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Hu J, Lin X, Gao P, Zhang Q, Zhou B, Wang O, Jiang Y, Xia W, Xing X, Li M. Genotypic and Phenotypic Spectrum and Pathogenesis of WNT1 Variants in a Large Cohort of Patients With OI/Osteoporosis. J Clin Endocrinol Metab 2023; 108:1776-1786. [PMID: 36595228 PMCID: PMC10271228 DOI: 10.1210/clinem/dgac752] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 12/12/2022] [Accepted: 12/23/2022] [Indexed: 01/04/2023]
Abstract
CONTEXT Mutations in WNT1 can cause rare inherited disorders such as osteogenesis imperfecta (OI) and early-onset osteoporosis (EOOP). Owing to its rarity, the clinical characteristics and pathogenic mechanism of WNT1 mutations remain unclear. OBJECTIVE We aimed to explore the phenotypic and genotypic spectrum and treatment responses of a large cohort of patients with WNT1-related OI/OP and the molecular mechanisms of WNT1 variants. METHODS The phenotypes and genotypes of patients and their responses to bisphosphonates or denosumab were evaluated. Western blot analysis, quantitative polymerase chain reaction, and immunofluorescence staining were used to evaluate the expression levels of WNT1, total β-catenin, and type I collagen in the tibial bone or skin from one patient. RESULTS We included 16 patients with 16 mutations identified in WNT1, including a novel mutation. The types of WNT1 mutations were related to skeletal phenotypes, and biallelic nonsense mutations or frameshift mutations could lead to an earlier occurrence of fragility fractures and more severe skeletal phenotypes. Some rare comorbidities were identified in this cohort, including cerebral abnormalities, hematologic diseases, and pituitary adenoma. Bisphosphonates and denosumab significantly increased the spine and proximal hip BMD of patients with WNT1 mutations and reshaped the compressed vertebrae. We report for the first time a decreased β-catenin level in the bone of patient 10 with c.677C > T and c.502G > A compared to the healthy control, which revealed the potential mechanisms of WNT1-induced skeletal phenotypes. CONCLUSION Biallelic nonsense mutations or frameshift mutations of WNT1 could lead to an earlier occurrence of fragility fractures and a more severe skeletal phenotype in OI and EOOP induced by WNT1 mutations. The reduced osteogenic activity caused by WNT pathway downregulation could be a potential pathogenic mechanism of WNT1-related OI and EOOP.
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Affiliation(s)
- Jing Hu
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xiaoyun Lin
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Peng Gao
- Department of Orthopedics, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing 100730, China
| | - Qian Zhang
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Bingna Zhou
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Ou Wang
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yan Jiang
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Weibo Xia
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xiaoping Xing
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Mei Li
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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Panzaru MC, Florea A, Caba L, Gorduza EV. Classification of osteogenesis imperfecta: Importance for prophylaxis and genetic counseling. World J Clin Cases 2023; 11:2604-2620. [PMID: 37214584 PMCID: PMC10198117 DOI: 10.12998/wjcc.v11.i12.2604] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 03/18/2023] [Accepted: 03/27/2023] [Indexed: 04/25/2023] Open
Abstract
Osteogenesis imperfecta (OI) is a genetically heterogeneous monogenic disease characterized by decreased bone mass, bone fragility, and recurrent fractures. The phenotypic spectrum varies considerably ranging from prenatal fractures with lethal outcomes to mild forms with few fractures and normal stature. The basic mechanism is a collagen-related defect, not only in synthesis but also in folding, processing, bone mineralization, or osteoblast function. In recent years, great progress has been made in identifying new genes and molecular mechanisms underlying OI. In this context, the classification of OI has been revised several times and different types are used. The Sillence classification, based on clinical and radiological characteristics, is currently used as a grading of clinical severity. Based on the metabolic pathway, the functional classification allows identifying regulatory elements and targeting specific therapeutic approaches. Genetic classification has the advantage of identifying the inheritance pattern, an essential element for genetic counseling and prophylaxis. Although genotype-phenotype correlations may sometimes be challenging, genetic diagnosis allows a personalized management strategy, accurate family planning, and pregnancy management decisions including options for mode of delivery, or early antenatal OI treatment. Future research on molecular pathways and pathogenic variants involved could lead to the development of genotype-based therapeutic approaches. This narrative review summarizes our current understanding of genes, molecular mechanisms involved in OI, classifications, and their utility in prophylaxis.
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Affiliation(s)
- Monica-Cristina Panzaru
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Andreea Florea
- Department of Medical Genetics - Medical Genetics resident, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Lavinia Caba
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Eusebiu Vlad Gorduza
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
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Peris P, Monegal A, Mäkitie RE, Guañabens N, González-Roca E. Osteoporosis related to WNT1 variants: a not infrequent cause of osteoporosis. Osteoporos Int 2023; 34:405-411. [PMID: 36396825 DOI: 10.1007/s00198-022-06609-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 11/10/2022] [Indexed: 11/19/2022]
Abstract
UNLABELLED Nearly 10% of subjects with severe idiopathic osteoporosis present pathogenic WNT1 mutations. Clinical characteristics include a family history of osteoporosis, early adulthood onset, and fragility fractures which may evolve to pseudoarthrosis. WNT1 should be genetically screened in these patients as the phenotype is often variable and therapeutic approaches may differ. INTRODUCTION Recent studies have shown that homozygous WNT1 gene mutations may be related to severe osteoporosis resembling osteogenesis imperfecta (OI). Conversely, heterozygous WNT1 mutations are linked to a milder phenotype of early-onset osteoporosis. Treatment with bisphosphonates is reported to be unsatisfactory. Our aim was to analyze the presence and prevalence of WNT1 mutations and the main associated clinical characteristics in subjects with primary early-onset osteoporosis. METHODS A cohort comprising 56 subjects (aged 19-60 years) with severe, early-onset osteoporosis was screened by massive parallel sequencing with a 23-gene panel. The gene panel included 19 genes known to cause OI (including the WNT1 gene), three genes related to osteoporosis, and the gene related to hypophosphatasia (ALPL). RESULTS We identified five patients (3 men) with heterozygous WNT1 variants. All presented severe osteoporosis with early fracture onset and a family history of fragility fractures. None presented a characteristic phenotype of OI or skeletal deformities. One patient was previously treated with bisphosphonates, presenting inadequate response to treatment and two developed pseudoarthrosis after upper arm fractures. All subjects were diagnosed in adulthood. CONCLUSIONS Nearly 1/10 adult subjects with severe idiopathic osteoporosis may present pathogenic WNT1 mutations. Clinical characteristics commonly include a family history of osteoporosis, onset in early adulthood, marked decrease in bone mass, and prevalent fractures, particularly vertebral. WNT1 should be genetically screened in these subjects as the phenotype is often variable and the therapeutic approach may differ. The role of WNT1 mutations in the development of pseudoarthrosis should also be elucidated.
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Affiliation(s)
- Pilar Peris
- Department of Rheumatology, Hospital Clínic, University of Barcelona, Villarroel 170, 08036, Barcelona, Spain.
| | - Ana Monegal
- Department of Rheumatology, Hospital Clínic, University of Barcelona, Villarroel 170, 08036, Barcelona, Spain
| | - Riikka E Mäkitie
- Folkhälsan Institute of Genetics, University of Helsinki, P.O. Box 63, FIN-00014, Helsinki, Finland
| | - Nuria Guañabens
- Department of Rheumatology, Hospital Clínic, University of Barcelona, Villarroel 170, 08036, Barcelona, Spain
| | - Eva González-Roca
- Department of Immunology, Hospital Clínic, University of Barcelona, Barcelona, Spain
- Department of Molecular Biology, CORE Laboratory, Hospital Clínic, University of Barcelona, Barcelona, Spain
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Zhu J, Liu K, He S, Yang Z, Song J, Ju Y, Xiong C, Zhang G, Yang W, Tang C. Type XV osteogenesis imperfecta: A novel mutation in the WNT1 gene, c.620G >A (p.R207H), is associated with an inner ear deformity. Intractable Rare Dis Res 2023; 12:58-61. [PMID: 36873675 PMCID: PMC9976088 DOI: 10.5582/irdr.2022.01099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 11/19/2022] [Accepted: 11/22/2022] [Indexed: 01/22/2023] Open
Abstract
The Wnt signaling pathway is vital in encouraging bone growth. WNT1 gene mutations have been identified as the major cause of type XV osteogenesis imperfecta (OI). Described here is a case of complex heterozygous WNT1 c.620G>A (p.R207H) and c.677C >T (p.S226L) OI caused by a novel mutation at locus c.620G >A (p.R207H). The female patient had type XV OI, distinguished by poor bone density, frequent fractures, a small stature, skull softening, lack of dentine hypoplasia, a brain malformation, and obvious blue sclera. A CT scan of the temporal bone revealed abnormalities of the inner ear, necessitating a hearing aid 8 months after birth. There was no family history of such disorders in the proband's parents. The proband inherited complex heterozygous WNT1 gene variants c.677C>T (p.S226L) and c.620G>A (p.R207H) from her father and mother, respectively. Presented here is a case of OI with inner ear deformation caused by c.620G>A (p.R207H), which is a novel WNT1 site mutation. This case broadens the genetic spectrum of OI and it provides a rationale for genetic testing of mothers and a medical consultation to estimate the risk of fetal illness.
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Affiliation(s)
- Jicai Zhu
- Department of Pediatrics, The First People's Hospital of Yunnan Province, Medical School & Affiliated Hospital, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Kai Liu
- Department of Pediatrics, The First People's Hospital of Yunnan Province, Medical School & Affiliated Hospital, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Shan He
- Department of Pediatrics, The First People's Hospital of Yunnan Province, Medical School & Affiliated Hospital, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Zihao Yang
- Medical School & Affiliated Hospital, Kunming University of Science and Technology. Department of Radiology, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Jiaying Song
- Medical School & Affiliated Hospital, Kunming University of Science and Technology. Department of Pediatrics, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Yan Ju
- Medical School & Affiliated Hospital, Kunming University of Science and Technology. Department of Pediatrics, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Caiyun Xiong
- Medical School & Affiliated Hospital, Kunming University of Science and Technology. Department of Pediatrics, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Guomei Zhang
- Department of Pediatrics, The First People's Hospital of Yunnan Province, Medical School & Affiliated Hospital, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Wen Yang
- Medical School & Affiliated Hospital, Kunming University of Science and Technology. Department of Pediatrics, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China
| | - Chunhui Tang
- Department of Pediatrics, The First People's Hospital of Yunnan Province, Medical School & Affiliated Hospital, Kunming University of Science and Technology, Kunming, Yunnan, China
- Address correspondence to:Chunhui Tang, Department of Pediatrics, The First People's Hospital of Yunnan Province, Kunming 650021, Yunnan, China. E-mail:
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11
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Costantini A, Mäkitie RE, Hartmann MA, Fratzl-Zelman N, Zillikens MC, Kornak U, Søe K, Mäkitie O. Early-Onset Osteoporosis: Rare Monogenic Forms Elucidate the Complexity of Disease Pathogenesis Beyond Type I Collagen. J Bone Miner Res 2022; 37:1623-1641. [PMID: 35949115 PMCID: PMC9542053 DOI: 10.1002/jbmr.4668] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 07/22/2022] [Accepted: 08/01/2022] [Indexed: 12/05/2022]
Abstract
Early-onset osteoporosis (EOOP), characterized by low bone mineral density (BMD) and fractures, affects children, premenopausal women and men aged <50 years. EOOP may be secondary to a chronic illness, long-term medication, nutritional deficiencies, etc. If no such cause is identified, EOOP is regarded primary and may then be related to rare variants in genes playing a pivotal role in bone homeostasis. If the cause remains unknown, EOOP is considered idiopathic. The scope of this review is to guide through clinical and genetic diagnostics of EOOP, summarize the present knowledge on rare monogenic forms of EOOP, and describe how analysis of bone biopsy samples can lead to a better understanding of the disease pathogenesis. The diagnostic pathway of EOOP is often complicated and extensive assessments may be needed to reliably exclude secondary causes. Due to the genetic heterogeneity and overlapping features in the various genetic forms of EOOP and other bone fragility disorders, the genetic diagnosis usually requires the use of next-generation sequencing to investigate several genes simultaneously. Recent discoveries have elucidated the complexity of disease pathogenesis both regarding genetic architecture and bone tissue-level pathology. Two rare monogenic forms of EOOP are due to defects in genes partaking in the canonical WNT pathway: LRP5 and WNT1. Variants in the genes encoding plastin-3 (PLS3) and sphingomyelin synthase 2 (SGMS2) have also been found in children and young adults with skeletal fragility. The molecular mechanisms leading from gene defects to clinical manifestations are often not fully understood. Detailed analysis of patient-derived transiliac bone biopsies gives valuable information to understand disease pathogenesis, distinguishes EOOP from other bone fragility disorders, and guides in patient management, but is not widely available in clinical settings. Despite the great advances in this field, EOOP remains an insufficiently explored entity and further research is needed to optimize diagnostic and therapeutic approaches. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Alice Costantini
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Paris Cité University, INSERM UMR1163, Institut Imagine, Paris, France
| | - Riikka E Mäkitie
- Folkhälsan Institute of Genetics, Helsinki, Finland.,Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Markus A Hartmann
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Vienna, Austria.,Vienna Bone and Growth Center, Vienna, Austria
| | - Nadja Fratzl-Zelman
- Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of OEGK and AUVA Trauma Centre Meidling, 1st Medical Department Hanusch Hospital, Vienna, Austria.,Vienna Bone and Growth Center, Vienna, Austria
| | - M Carola Zillikens
- Bone Center, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Uwe Kornak
- Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
| | - Kent Søe
- Clinical Cell Biology, Department of Pathology, Odense University Hospital, Odense, Denmark.,Clinical Cell Biology, Pathology Research Unit, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.,Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Outi Mäkitie
- Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Folkhälsan Institute of Genetics, Helsinki, Finland.,Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Children's Hospital and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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12
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Abstract
Osteoporosis is a skeletal disorder with enhanced bone fragility, usually affecting the elderly. It is very rare in children and young adults and the definition is not only based on a low BMD (a Z-score < - 2.0 in growing children and a Z-score ≤ - 2.0 or a T-score ≤ - 2.5 in young adults) but also on the occurrence of fragility fractures and/or the existence of underlying chronic diseases or secondary factors such as use of glucocorticoids. In the absence of a known chronic disease, fragility fractures and low BMD should prompt extensive screening for secondary causes, which can be found in up to 90% of cases. When fragility fractures occur in childhood or young adulthood without an evident secondary cause, investigations should explore the possibility of an underlying monogenetic bone disease, where bone fragility is caused by a single variant in a gene that has a major role in the skeleton. Several monogenic forms relate to type I collagen, but other forms also exist. Loss-of-function variants in LRP5 and WNT1 may lead to early-onset osteoporosis. The X-chromosomal osteoporosis caused by PLS3 gene mutations affects especially males. Another recently discovered form relates to disturbed sphingolipid metabolism due to SGMS2 mutations, underscoring the complexity of molecular pathology in monogenic early-onset osteoporosis. Management of young patients consists of treatment of secondary factors, optimizing lifestyle factors including calcium and vitamin D and physical exercise. Treatment with bone-active medication should be discussed on a personalized basis, considering the severity of osteoporosis and underlying disease versus the absence of evidence on anti-fracture efficacy and potential harmful effects in pregnancy.
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Affiliation(s)
- Outi Mäkitie
- Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- Folkhälsan Research Center, Biomedicum Helsinki, P.O. Box 63, FI-00014, Helsinki, Finland.
| | - M Carola Zillikens
- Department of Internal Medicine, Erasmus University Medical Center, 3015, Rotterdam, The Netherlands
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13
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Jovanovic M, Guterman-Ram G, Marini JC. Osteogenesis Imperfecta: Mechanisms and Signaling Pathways Connecting Classical and Rare OI Types. Endocr Rev 2022; 43:61-90. [PMID: 34007986 PMCID: PMC8755987 DOI: 10.1210/endrev/bnab017] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Osteogenesis imperfecta (OI) is a phenotypically and genetically heterogeneous skeletal dysplasia characterized by bone fragility, growth deficiency, and skeletal deformity. Previously known to be caused by defects in type I collagen, the major protein of extracellular matrix, it is now also understood to be a collagen-related disorder caused by defects in collagen folding, posttranslational modification and processing, bone mineralization, and osteoblast differentiation, with inheritance of OI types spanning autosomal dominant and recessive as well as X-linked recessive. This review provides the latest updates on OI, encompassing both classical OI and rare forms, their mechanism, and the signaling pathways involved in their pathophysiology. There is a special emphasis on mutations in type I procollagen C-propeptide structure and processing, the later causing OI with strikingly high bone mass. Types V and VI OI, while notably different, are shown to be interrelated by the interferon-induced transmembrane protein 5 p.S40L mutation that reveals the connection between the bone-restricted interferon-induced transmembrane protein-like protein and pigment epithelium-derived factor pathways. The function of regulated intramembrane proteolysis has been extended beyond cholesterol metabolism to bone formation by defects in regulated membrane proteolysis components site-2 protease and old astrocyte specifically induced-substance. Several recently proposed candidate genes for new types of OI are also presented. Discoveries of new OI genes add complexity to already-challenging OI management; current and potential approaches are summarized.
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Affiliation(s)
- Milena Jovanovic
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Gali Guterman-Ram
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Joan C Marini
- Section on Heritable Disorders of Bone and Extracellular Matrix, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
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14
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Campopiano MC, Fogli A, Michelucci A, Mazoni L, Longo A, Borsari S, Pardi E, Benelli E, Sardella C, Pierotti L, Dinoi E, Marcocci C, Cetani F. Case report: Early-onset osteoporosis in a patient carrying a novel heterozygous variant of the WNT1 gene. Front Endocrinol (Lausanne) 2022; 13:918682. [PMID: 36004351 PMCID: PMC9393300 DOI: 10.3389/fendo.2022.918682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 07/14/2022] [Indexed: 12/02/2022] Open
Abstract
The WNT1 gene is crucial for bone development and homeostasis. Homozygous mutations in WNT1 cause severe bone fragility known as osteogenesis imperfecta type XV. Moreover, heterozygous WNT1 mutations have been found in adults with early-onset osteoporosis. We identified a 35 year-old Caucasian woman who experienced multiple vertebral fractures two months after her second pregnancy. There was no history of risk factors for secondary osteoporosis or family history of osteoporosis. Dual-energy X-ray absorptiometry confirmed a marked reduction of bone mineral density (BMD) at the lumbar spine (0.734 g/cm2, Z-score -2.8), femoral neck (0.48 g/cm2, Z-score -3.5), and total hip (0.589 g/cm2, Z-score -3.0). Blood tests excluded secondary causes of bone fragility. Genetic analysis revealed a heterozygous missense mutation (p.Leu370Val) in the WNT1 gene. Varsome classified it as a variant of uncertain significance. However, the fact that the Leucine residue at position 370 is highly conserved among vertebrate species and the variant has a very low allelic frequency in the general population would exclude the possibility of a polymorphism. The patient was treated for two years with teriparatide therapy associated with calcium and vitamin D supplements. During the follow-up period she did not report further clinical fractures. After 24 months of teriparatide, BMD increased at lumbar spine (+14.6%), femoral neck (+8.3%) and total hip (+4.9%) compared to baseline. We confirm that the heterozygous WNT1 mutation could cause a variable bone fragility and low turnover osteoporosis. We suggest that teriparatide is one of the most appropriate available therapies for this case.
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Affiliation(s)
- Maria Cristina Campopiano
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Pisa, Italy
| | - Antonella Fogli
- Laboratory of Molecular Genetics, University Hospital of Pisa, Pisa, Italy
| | - Angela Michelucci
- Laboratory of Molecular Genetics, University Hospital of Pisa, Pisa, Italy
| | - Laura Mazoni
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Pisa, Italy
| | - Antonella Longo
- Department of Biological Sciences and BioDiscovery Institute, University of North Texas, Denton, TX, United States
| | - Simona Borsari
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Pisa, Italy
| | - Elena Pardi
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Pisa, Italy
| | - Elena Benelli
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Pisa, Italy
| | - Chiara Sardella
- Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy
| | - Laura Pierotti
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Pisa, Italy
| | - Elisa Dinoi
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Pisa, Italy
| | - Claudio Marcocci
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Pisa, Pisa, Italy
- Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy
| | - Filomena Cetani
- Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy
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15
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Li S, Cao Y, Wang H, Li L, Ren X, Mi H, Wang Y, Guan Y, Zhao F, Mao B, Yang T, You Y, Guan X, Yang Y, Zhang X, Zhao X. Genotypic and Phenotypic Analysis in Chinese Cohort With Autosomal Recessive Osteogenesis Imperfecta. Front Genet 2020; 11:984. [PMID: 33093841 PMCID: PMC7523636 DOI: 10.3389/fgene.2020.00984] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 08/04/2020] [Indexed: 11/13/2022] Open
Abstract
Osteogenesis imperfecta (OI) is a rare heritable skeletal disorder which is mainly caused by defected type I collagen. Autosomal recessive OI (AR-OI) is caused by mutations of genes that are responsible for type I collagen modification and folding, and is often associated with more severe phenotypes. Due to the limited number of recessive OI patients, it has been difficult to study the mutation spectrum as well as the correlation of genotype and phenotype. This study recruited a Chinese cohort of 74 AR-OI families, aiming to establish the mutation spectrum and to examine the genotypic and phenotypic correlation. We identified 82 variants including 25 novel variants and 57 HGMD reported variants in these AR-OI patients, using whole exome sequencing/panel sequencing combined with Sanger sequencing. Pathogenic mutations were found at WNT1 (n = 30, 40.54%), SERPINF1 (n = 22, 29.73%), FKBP10 (n = 10, 13.51%), CRTAP (n = 3, 4.05%), P3H1 (n = 3, 4.05%), SERPINH1 (n = 2, 2.70%), SEC24D (n = 3, 4.05%), and PLOD2 (n = 1, 1.35%) respectively. Thus, WNT1 represents the most frequent pathogenic gene of AR-OI in Chinese population. The most common clinical manifestations of AR-OI patients include walking problem (72.86%), scoliosis (65.28%) and frequent fractures (fractures ≥2/year) (54.05%). Interestingly, ptosis represents a unique phenotype of patients carrying WNT1 variants, and it was rare in patients harboring other pathogenic genes. Our study expanded the mutation spectrum of AR-OI and enriched the knowledge of genotypic and phenotypic correlation in Chinese cohort with AR-OI.
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Affiliation(s)
- Shan Li
- Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yixuan Cao
- Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Han Wang
- Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Lulu Li
- Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Xiuzhi Ren
- The People's Hospital of Wuqing District, Tianjin, China
| | - Huan Mi
- Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yanzhou Wang
- Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Yun Guan
- Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Feiyue Zhao
- Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Bin Mao
- Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Tao Yang
- Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yi You
- Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Xin Guan
- Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yujiao Yang
- Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Xue Zhang
- Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Xiuli Zhao
- Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China
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16
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Chen P, Chen J, Yang Z, Lu Y, Shen L, Zhou K, Ye S, Shen B. Consanguineous-derived homozygous WNT1 mutation results in osteogenesis imperfect with congenital ptosis and exotropia. Mol Genet Genomic Med 2020; 8:e1350. [PMID: 32529806 PMCID: PMC7434602 DOI: 10.1002/mgg3.1350] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/12/2020] [Accepted: 05/19/2020] [Indexed: 02/04/2023] Open
Abstract
Background Wnt signaling pathway plays an important role in promoting ostergenesis. WNT1 mutations have been considered as a major cause of ostergenesis imperfect (OI). We identified an OI patient with pathogenic consanguineous‐derived homozygous WNT1 missense mutation. Methods We designed and applied a panel of known 261 genes associated with hereditary bone diseases for targeted next‐generation sequencing to examine clinically diagnosed OI patients. Detected mutations were confirmed by Sanger sequencing. Results The female proband presented with severe OI with low bone density, multiple long bone fractures, short stature, and absence of dentinogenesis imperfect and brain malformation. She had congenital ptosis and exotropia with her left eye, and absence of blue sclera. The proband came from a consanguineous family and had a homozygous WNT1 missense mutation (c.677C>T, (p.S226L)). In addition, three other compound heterozygous mutations (c.1729C>T in FKBP10, c.1958A>C in FGFR3, c.760G>C in TRPV4) were also detected in her family members. Conclusion We report the first identified case of consanguineous derived homozygous WNT1 mutation leading to severe osteogenesis imperfecta with congenital ptosis and exotropia.
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Affiliation(s)
- Peng Chen
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Lin Hai, P.R. China
| | - Jiaxi Chen
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Lin Hai, P.R. China
| | - Zhantao Yang
- Continuing Medical Education and Research Center, Dian Diagnostics Group Co., Ltd., Hangzhou, P.R. China
| | - Yang Lu
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Lin Hai, P.R. China
| | - Liping Shen
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Lin Hai, P.R. China
| | - Kai Zhou
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Lin Hai, P.R. China
| | - Shenyi Ye
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Lin Hai, P.R. China
| | - Bo Shen
- Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Lin Hai, P.R. China
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