|
1
|
Goyal S, Tibrewal S, Ratna R, Vanita V. Genetic and environmental factors contributing to anophthalmia and microphthalmia: Current understanding and future directions. World J Clin Pediatr 2025; 14:101982. [DOI: 10.5409/wjcp.v14.i2.101982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 02/19/2025] [Accepted: 02/25/2025] [Indexed: 03/18/2025] Open
Abstract
Anophthalmia is defined as a complete absence of one eye or both the eyes, while microphthalmia represents the presence of a small eye within the orbit. The estimated birth prevalence for anophthalmia is approximately 3 per 100000 live births, and for microphthalmia, it is around 14 per 100000 live births. However, combined evidence suggests that the prevalence of these malformations could be as high as 30 per 100000 individuals. Microphthalmia is reported to occur in 3.2% to 11.2% of blind children. Anophthalmia and microphthalmia (A/M) are part of a phenotypic spectrum alongside ocular coloboma, hypothesized to share a common genetic basis. Both A/M can occur in isolation or as part of a syndrome. Their complex etiology involves chromosomal aberrations, monogenic inheritance pattern, and the contribution of environmental factors such as gestational-acquired infections, maternal vitamin A deficiency (VAD), exposure to X-rays, solvent misuse, and thalidomide exposure. A/M exhibit significant clinical and genetic heterogeneity with over 90 genes identified so far. Familial cases of A/M have a complex genetic basis, including all Mendelian modes of inheritance, i.e., autosomal dominant, recessive, and X-linked. Most cases arise sporadically due to de novo mutations. Examining gene expression during eye development and the effects of various environmental variables will help us better understand the phenotypic heterogeneity found in A/M, leading to more effective diagnosis and management strategies. The present review focuses on key genetic factors, developmental abnormalities, and environmental modifiers linked with A/M. It also emphasizes at potential research areas including multiomic methods and disease modeling with induced pluripotent stem cell technologies, which aim to create innovative treatment options.
Collapse
Affiliation(s)
- Shiwali Goyal
- Department of Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Rockville, MD 20852, United States
| | - Shailja Tibrewal
- Department of Pediatric Ophthalmology, Dr. Shroff’s Charity Eye Hospital, New Delhi 110002, Delhi, India
- Department of Ocular Genetics (Center for Unknown and Rare Eye Diseases), Dr. Shroff’s Charity Eye Hospital, New Delhi 110002, Delhi, India
| | - Ria Ratna
- Department of Ocular Genetics (Center for Unknown and Rare Eye Diseases), Dr. Shroff’s Charity Eye Hospital, New Delhi 110002, Delhi, India
| | - Vanita Vanita
- Department of Human Genetics, Guru Nanak Dev University, Amritsar 143005, Punjab, India
| |
Collapse
|
|
2
|
Ulrich E, Kistenmacher S, Martin G, Schlötzer-Schrehardt U, Seitz B, Auw-Hädrich C, Schlunck G, Reinhard T, Polisetti N. PAX3 expression patterns in ocular surface melanocytes. Sci Rep 2025; 15:12472. [PMID: 40216818 PMCID: PMC11992251 DOI: 10.1038/s41598-025-90318-3] [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: 11/01/2024] [Accepted: 02/12/2025] [Indexed: 04/14/2025] Open
Abstract
PAX3, a transcription factor essential for neural crest development and melanocyte progenitors, is expressed in various melanocytic tissues. However, its role in ocular surface tissues remains poorly understood. This study investigated the expression patterns of PAX3 in the limbal stem cell niche, specifically in limbal epithelial progenitor cells (LEPC), limbal melanocytes (LM), and limbal mesenchymal stem cells (LMSC). Additionally, PAX3 expression was studied in conjunctival/limbal melanoma specimens. Immunohistochemical analysis revealed predominant PAX3 expression in LM as well in the conjunctival melanocytes, suggesting distinct roles in stem cell regulation and melanocyte maintenance. Notably, PAX3 was significantly upregulated in conjunctival/limbal melanoma tissues compared to healthy counterparts, with expression co-localizing with melanocyte markers (Melan-A, HMB45, SOX10) and the proliferation marker Ki-67 in melanoma cells. These findings suggests that while PAX3 expression is restricted to melanocytes in limbal/conjunctival tissues and its dysregulation may play a crucial role in conjunctival/limbal melanoma development. Further investigation into mechanisms by which PAX3 influences corneal pathophysiology and contributes to conjunctival/limbal melanoma pathogenesis could identify potential therapeutic targets for this aggressive ocular malignancy.
Collapse
Affiliation(s)
- Eva Ulrich
- Eye Center, Medical Center - Faculty of Medicine, University of Freiburg, Killianstrasse 5, 79106, Freiburg, Germany
| | - Sebastian Kistenmacher
- Eye Center, Medical Center - Faculty of Medicine, University of Freiburg, Killianstrasse 5, 79106, Freiburg, Germany
| | - Gottfried Martin
- Eye Center, Medical Center - Faculty of Medicine, University of Freiburg, Killianstrasse 5, 79106, Freiburg, Germany
| | | | - Berthold Seitz
- Department of Ophthalmology, Saarland University Medical Center, Homburg, Saar, Germany
| | - Claudia Auw-Hädrich
- Eye Center, Medical Center - Faculty of Medicine, University of Freiburg, Killianstrasse 5, 79106, Freiburg, Germany
| | - Günther Schlunck
- Eye Center, Medical Center - Faculty of Medicine, University of Freiburg, Killianstrasse 5, 79106, Freiburg, Germany
| | - Thomas Reinhard
- Eye Center, Medical Center - Faculty of Medicine, University of Freiburg, Killianstrasse 5, 79106, Freiburg, Germany
| | - Naresh Polisetti
- Eye Center, Medical Center - Faculty of Medicine, University of Freiburg, Killianstrasse 5, 79106, Freiburg, Germany.
| |
Collapse
|
|
3
|
Shaw T, Barr FG, Üren A. The PAX Genes: Roles in Development, Cancer, and Other Diseases. Cancers (Basel) 2024; 16:1022. [PMID: 38473380 PMCID: PMC10931086 DOI: 10.3390/cancers16051022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 02/28/2024] [Accepted: 02/28/2024] [Indexed: 03/14/2024] Open
Abstract
Since their 1986 discovery in Drosophila, Paired box (PAX) genes have been shown to play major roles in the early development of the eye, muscle, skeleton, kidney, and other organs. Consistent with their roles as master regulators of tissue formation, the PAX family members are evolutionarily conserved, regulate large transcriptional networks, and in turn can be regulated by a variety of mechanisms. Losses or mutations in these genes can result in developmental disorders or cancers. The precise mechanisms by which PAX genes control disease pathogenesis are well understood in some cases, but much remains to be explored. A deeper understanding of the biology of these genes, therefore, has the potential to aid in the improvement of disease diagnosis and the development of new treatments.
Collapse
Affiliation(s)
- Taryn Shaw
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20001, USA
| | - Frederic G Barr
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA
| | - Aykut Üren
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20001, USA
| |
Collapse
|
|
4
|
Miyadai M, Takada H, Shiraishi A, Kimura T, Watakabe I, Kobayashi H, Nagao Y, Naruse K, Higashijima SI, Shimizu T, Kelsh RN, Hibi M, Hashimoto H. A gene regulatory network combining Pax3/7, Sox10 and Mitf generates diverse pigment cell types in medaka and zebrafish. Development 2023; 150:dev202114. [PMID: 37823232 PMCID: PMC10617610 DOI: 10.1242/dev.202114] [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: 06/23/2023] [Accepted: 09/11/2023] [Indexed: 10/13/2023]
Abstract
Neural crest cells generate numerous derivatives, including pigment cells, and are a model for studying how fate specification from multipotent progenitors is controlled. In mammals, the core gene regulatory network for melanocytes (their only pigment cell type) contains three transcription factors, Sox10, Pax3 and Mitf, with the latter considered a master regulator of melanocyte development. In teleosts, which have three to four pigment cell types (melanophores, iridophores and xanthophores, plus leucophores e.g. in medaka), gene regulatory networks governing fate specification are poorly understood, although Mitf function is considered conserved. Here, we show that the regulatory relationships between Sox10, Pax3 and Mitf are conserved in zebrafish, but the role for Mitf is more complex than previously emphasized, affecting xanthophore development too. Similarly, medaka Mitf is necessary for melanophore, xanthophore and leucophore formation. Furthermore, expression patterns and mutant phenotypes of pax3 and pax7 suggest that Pax3 and Pax7 act sequentially, activating mitf expression. Pax7 modulates Mitf function, driving co-expressing cells to differentiate as xanthophores and leucophores rather than melanophores. We propose that pigment cell fate specification should be considered to result from the combinatorial activity of Mitf with other transcription factors.
Collapse
Affiliation(s)
- Motohiro Miyadai
- Laboratory of Biological Science, Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan
| | - Hiroyuki Takada
- Laboratory of Biological Science, Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan
| | - Akiko Shiraishi
- Laboratory of Biological Science, Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan
| | - Tetsuaki Kimura
- Laboratory of Bioresources, National Institute for Basic Biology, Okazaki 444-8585, Japan
| | - Ikuko Watakabe
- National Institutes of Natural Sciences, Exploratory Research Center on Life and Living Systems, National Institute for Basic Biology, Okazaki 444-8787, Japan
| | - Hikaru Kobayashi
- Laboratory of Biological Science, Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan
| | - Yusuke Nagao
- Laboratory of Biological Science, Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan
| | - Kiyoshi Naruse
- Laboratory of Bioresources, National Institute for Basic Biology, Okazaki 444-8585, Japan
| | - Shin-ichi Higashijima
- National Institutes of Natural Sciences, Exploratory Research Center on Life and Living Systems, National Institute for Basic Biology, Okazaki 444-8787, Japan
| | - Takashi Shimizu
- Laboratory of Biological Science, Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan
| | - Robert N. Kelsh
- Department of Life Sciences, University of Bath, Bath BA2 7AY, UK
| | - Masahiko Hibi
- Laboratory of Biological Science, Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan
| | - Hisashi Hashimoto
- Laboratory of Biological Science, Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan
| |
Collapse
|
|
5
|
Knebel D, Rudolph G, Herold T, Priglinger S. [Waardenburg's Syndrome Type IIA with Partial Albinism]. Klin Monbl Augenheilkd 2022; 239:1467-1470. [PMID: 34571549 DOI: 10.1055/a-1610-9690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Dominik Knebel
- Augenklinik und Poliklinik, Klinikum der Universität München, Deutschland
| | - Günter Rudolph
- Augenklinik und Poliklinik, Klinikum der Universität München, Deutschland
| | - Tina Herold
- Augenklinik und Poliklinik, Klinikum der Universität München, Deutschland
| | | |
Collapse
|
|
6
|
Murakami S, Tsuchiya K, Nakata K, Nishikata M, Kitada K, Suzuki H. A Kit Mutation Associated with Black-Eyed White Phenotype in the Grey Red-Backed Vole, Myodes rufocanus. MAMMAL STUDY 2022. [DOI: 10.3106/ms2022-0003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Affiliation(s)
- Shota Murakami
- Graduate School of Environmental Science, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Kimiyuki Tsuchiya
- Laboratory of Bioresources, Applied Biology Co. Ltd, Minato-ku, Tokyo, Japan
| | - Keisuke Nakata
- Forestry Research Institute, Hokkaido Research Organization, Bibai, Hokkaido, Japan
| | - Mana Nishikata
- Graduate School of Life Science, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Kazuhiro Kitada
- Graduate School of Life Science, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Hitoshi Suzuki
- Graduate School of Environmental Science, Hokkaido University, Sapporo, Hokkaido, Japan
| |
Collapse
|
|
7
|
Genetic insights, disease mechanisms, and biological therapeutics for Waardenburg syndrome. Gene Ther 2022; 29:479-497. [PMID: 33633356 DOI: 10.1038/s41434-021-00240-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 01/18/2021] [Accepted: 02/03/2021] [Indexed: 02/06/2023]
Abstract
Waardenburg syndrome (WS), also known as auditory-pigmentary syndrome, is the most common cause of syndromic hearing loss (HL), which accounts for approximately 2-5% of all patients with congenital hearing loss. WS is classified into four subtypes depending on the clinical phenotypes. Currently, pathogenic mutations of PAX3, MITF, SOX10, EDN3, EDNRB or SNAI2 are associated with different subtypes of WS. Although supportive techniques like hearing aids, cochlear implants, or other assistive listening devices can alleviate the HL symptom, there is no cure for WS to date. Recently major progress has been achieved in preclinical studies of genetic HL in animal models, including gene delivery and stem cell replacement therapies. This review focuses on the current understandings of pathogenic mechanisms and potential biological therapeutic approaches for HL in WS, providing strategies and directions for implementing WS biological therapies, as well as possible problems to be faced, in the future.
Collapse
|
|
8
|
Zhang L, Wan Y, Wang N. Waardenburg syndrome type 4 coexisting with open-angle glaucoma: a case report. J Med Case Rep 2022; 16:264. [PMID: 35790984 PMCID: PMC9258067 DOI: 10.1186/s13256-022-03460-1] [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: 01/12/2022] [Accepted: 05/16/2022] [Indexed: 11/25/2022] Open
Abstract
Background Waardenburg syndrome is an autosomal dominant disorder with varying degrees of sensorineural hearing loss as well as abnormal pigmentation in hair, skin, and iris. There are four types of Waardenburg syndrome (1–4) with different characteristics. Mutations in six genes have been identified to be associated with the various types. Herein, we describe a case of Waardenburg syndrome type 4 combined with open-angle glaucoma. Case presentation A 43-year-old Han Chinese man had undergone trabeculectomy due to progression of visual field impairment and unstable intraocular pressure in both eyes. Slit-lamp examination revealed diffuse iris hypopigmentation in the left eye and hypopigmentation of part of the iris in the right eye. Fundus examination showed red, sunset-like fundus due to a lack of pigmentation in the retinal pigment epithelium layer, diffuse loss of the nerve fiber layer, and an excavated optic nerve head with advanced-stage glaucoma. Imaging was performed using anterior segment optical coherence tomography to detect the iris configuration. In the heterochromic iris portion, the normal part of the iris showed a clear hyperreflective signal of the anterior border layer, while atrophy of the pigmented anterior border layer showed a hyporeflective area of the anterior surface resulting in reduced light absorption. Two mutations of the endothelin receptor type B gene were recognized in this study. The first (c.1111G>A on exon 7) leads to an amino acid change from glycine to serine at codon 371. Sanger verification revealed that this mutation is inherited from the mother. The other mutation (c.553G>A) leads to an amino acid change from valine to methionine at codon 185. Sanger verification showed that this mutation was inherited from the father. Conclusion Waardenburg syndrome shows a remarkable diversity in clinical presentation and morphology. This disease can also present with open-angle glaucoma. Sequencing analysis revealed two heterozygous mutations in the EDNRB gene in this patient, inherited from his mother and father, respectively. These two sites constitute a compound heterozygous variation.
Collapse
Affiliation(s)
- Li Zhang
- Beijing Institute of Ophthalmology, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, 17 Hougou Line, Chongnei Street, Dongcheng District, Beijing, 100005, China.
| | - Yue Wan
- Beijing Institute of Ophthalmology, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, 17 Hougou Line, Chongnei Street, Dongcheng District, Beijing, 100005, China
| | - Ningli Wang
- Beijing Institute of Ophthalmology, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, 17 Hougou Line, Chongnei Street, Dongcheng District, Beijing, 100005, China
| |
Collapse
|
|
9
|
Zug R. Developmental disorders caused by haploinsufficiency of transcriptional regulators: a perspective based on cell fate determination. Biol Open 2022; 11:bio058896. [PMID: 35089335 PMCID: PMC8801891 DOI: 10.1242/bio.058896] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Many human birth defects and neurodevelopmental disorders are caused by loss-of-function mutations in a single copy of transcription factor (TF) and chromatin regulator genes. Although this dosage sensitivity has long been known, how and why haploinsufficiency (HI) of transcriptional regulators leads to developmental disorders (DDs) is unclear. Here I propose the hypothesis that such DDs result from defects in cell fate determination that are based on disrupted bistability in the underlying gene regulatory network (GRN). Bistability, a crucial systems biology concept to model binary choices such as cell fate decisions, requires both positive feedback and ultrasensitivity, the latter often achieved through TF cooperativity. The hypothesis explains why dosage sensitivity of transcriptional regulators is an inherent property of fate decisions, and why disruption of either positive feedback or cooperativity in the underlying GRN is sufficient to cause disease. I present empirical and theoretical evidence in support of this hypothesis and discuss several issues for which it increases our understanding of disease, such as incomplete penetrance. The proposed framework provides a mechanistic, systems-level explanation of HI of transcriptional regulators, thus unifying existing theories, and offers new insights into outstanding issues of human disease. This article has an associated Future Leader to Watch interview with the author of the paper.
Collapse
Affiliation(s)
- Roman Zug
- Department of Biology, Lund University, 22362 Lund, Sweden
| |
Collapse
|
|
10
|
Zhang S, Lin S, Liu Z, Wang W, Li J, Chen Q, Yang L, Wang C, Pang Q. Case report: Heterogeneous mutations of SOX10 gene in a Chinese infant with Waardenburg syndrome type 4C. Front Pediatr 2022; 10:898693. [PMID: 36071884 PMCID: PMC9441800 DOI: 10.3389/fped.2022.898693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
A 5-month-old patient presented with grayish-blue iris bilaterally, skin and mucosal pigmentation loss, Hirschsprung's disease, full-blown growth retardation, and sensorineural deafness. The patient's whole exon gene sequencing revealed a spontaneous heterozygous code-shifting mutation in the SOX10 gene: c.803del:p.K268Sfs*18. The parents of the child were wild-type, and the site of the mutation is novel.
Collapse
Affiliation(s)
- Suli Zhang
- Department of Neuroscience, Hainan Women and Children's Medical Center, Haikou, China
| | - Shuangzhu Lin
- First Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Zhenxian Liu
- First Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Wanqi Wang
- Changchun University of Chinese Medicine, Changchun, China
| | - Jiayi Li
- Changchun University of Chinese Medicine, Changchun, China
| | - Qiandui Chen
- Changchun University of Chinese Medicine, Changchun, China
| | - Li Yang
- Department of Neuroscience, Hainan Women and Children's Medical Center, Haikou, China
| | - Cui Wang
- Department of Neuroscience, Hainan Women and Children's Medical Center, Haikou, China
| | - Qiming Pang
- Department of Neuroscience, Hainan Women and Children's Medical Center, Haikou, China
| |
Collapse
|
|
11
|
An L1 retrotransposon insertion-induced deafness mouse model for studying the development and function of the cochlear stria vascularis. Proc Natl Acad Sci U S A 2021; 118:2107933118. [PMID: 34583993 DOI: 10.1073/pnas.2107933118] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/20/2021] [Indexed: 01/23/2023] Open
Abstract
Dysregulation of ion and potential homeostasis in the scala media is the most prevalent cause of hearing loss in mammals. However, it is not well understood how the development and function of the stria vascularis regulates this fluid homeostasis in the scala media. From a mouse genetic screen, we characterize a mouse line, named 299, that displays profound hearing impairment. Histology suggests that 299 mutant mice carry a severe, congenital structural defect of the stria vascularis. The in vivo recording of 299 mice using double-barreled electrodes shows that endocochlear potential is abolished and potassium concentration is reduced to ∼20 mM in the scala media, a stark contrast to the +80 mV endocochlear potential and the 150 mM potassium concentration present in healthy control mice. Genomic analysis revealed a roughly 7-kb-long, interspersed nuclear element (LINE-1 or L1) retrotransposon insertion on chromosome 11. Strikingly, the deletion of this L1 retrotransposon insertion from chromosome 11 restored the hearing of 299 mutant mice. In summary, we characterize a mouse model that enables the study of stria vascularis development and fluid homeostasis in the scala media.
Collapse
|
|
12
|
A novel PAX3 mutation in a Chinese Han family with Waardenburg syndrome type 1. Int J Pediatr Otorhinolaryngol 2021; 147:110758. [PMID: 34038854 DOI: 10.1016/j.ijporl.2021.110758] [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: 10/20/2020] [Revised: 04/28/2021] [Accepted: 05/06/2021] [Indexed: 11/22/2022]
Abstract
OBJECTIVES To determine the clinical characteristics and genetic causes of Waardenburg syndrome type 1 (WS1) present in a Chinese Han family. METHODS Evaluations, including the familial history, clinical features and audiological tests, were performed on the proband and her parents. Genetic analyses were conducted using targeted next-generation sequencing of 144 known deafness genes, and confirmed by Sanger sequencing. Bioinformatics analyses of the candidate variant were performed. RESULTS The proband suffered from moderate hearing loss of the right ear, and her mother suffered from profound congenital bilateral hearing loss. The proband exhibited a left blue iris. The calculated W index of the proband was 2.61, while her mother's W index was 2.12. The proband and her mother were diagnosed with WS1 according to the Waardenburg Syndrome Consortium criteria. A novel missense variant NM_181457.3: c.127G > T; p.(Gly43Cys) in exon 2 in Paired Box 3 (PAX3) was identified in the proband and her mother, but this variant was not detected in the father and the controls. This variant was not reported in the HGMD, ClinVar, 1000G and ESP6500 databases. CONCLUSION We identified a novel missense variant in exon 2 of PAX3 as the genetic cause of WS1 in this two-generation family, which broadened the genetic spectrum of WS1.
Collapse
|
|
13
|
Abstract
Congenital hearing loss is the most common birth defect, estimated to affect 2-3 in every 1000 births. Currently there is no cure for hearing loss. Treatment options are limited to hearing aids for mild and moderate cases, and cochlear implants for severe and profound hearing loss. Here we provide a literature overview of the environmental and genetic causes of congenital hearing loss, common animal models and methods used for hearing research, as well as recent advances towards developing therapies to treat congenital deafness. © 2021 The Authors.
Collapse
Affiliation(s)
- Justine M Renauld
- Department of Otolaryngology, Head & Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Martin L Basch
- Department of Otolaryngology, Head & Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, Ohio.,Department of Genetics and Genome Sciences, Case Western Reserve School of Medicine, Cleveland, Ohio.,Department of Biology, Case Western Reserve University, Cleveland, Ohio.,Department of Otolaryngology, Head & Neck Surgery, University Hospitals, Cleveland, Ohio
| |
Collapse
|
|
14
|
Zhang S, Xu H, Tian Y, Liu D, Hou X, Zeng B, Chen B, Liu H, Li R, Li X, Zuo B, Tang R, Tang W. High Genetic Heterogeneity in Chinese Patients With Waardenburg Syndrome Revealed by Next-Generation Sequencing. Front Genet 2021; 12:643546. [PMID: 34149797 PMCID: PMC8212959 DOI: 10.3389/fgene.2021.643546] [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: 12/18/2020] [Accepted: 04/23/2021] [Indexed: 01/08/2023] Open
Abstract
Objective This study aimed to explore the genetic causes of probands who were diagnosed with Waardenburg syndrome (WS) or congenital sensorineural hearing loss. Methods A detailed physical and audiological examinations were carried out to make an accurate diagnosis of 14 patients from seven unrelated families. We performed whole-exome sequencing in probands to detect the potential genetic causes and further validated them by Sanger sequencing in the probands and their family members. Results The genetic causes for all 14 patients with WS or congenital sensorineural hearing loss were identified. A total of seven heterozygous variants including c.1459C > T, c.123del, and c.959-409_1173+3402del of PAX3 gene (NM_181459.4), c.198_262del and c.529_556del of SOX10 gene (NM_006941.4), and c.731G > A and c.970dup of MITF gene (NM_000248.3) were found for the first time. Of these mutations, we had confirmed two (c.1459C > T and c.970dup) are de novo by Sanger sequencing of variants in the probands and their parents. Conclusion We revealed a total of seven novel mutations in PAX3, SOX10, and MITF, which underlie the pathogenesis of WS. The clinical and genetic characterization of these families with WS elucidated high heterogeneity in Chinese patients with WS. This study expands the database of PAX3, SOX10, and MITF mutations and improves our understanding of the causes of WS.
Collapse
Affiliation(s)
- Sen Zhang
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Hongen Xu
- Precision Medicine Center, Academy of Medical Science, Zhengzhou University, Zhengzhou, China.,The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yongan Tian
- BGI College, Zhengzhou University, Zhengzhou, China
| | - Danhua Liu
- The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xinyue Hou
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Beiping Zeng
- BGI College, Zhengzhou University, Zhengzhou, China
| | - Bei Chen
- Department of Otology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Huanfei Liu
- Precision Medicine Center, Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Ruijun Li
- Precision Medicine Center, Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Xiaohua Li
- Department of Otology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Bin Zuo
- Department of Otology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ryan Tang
- Johns Hopkins University, Maryland, MD, United States
| | - Wenxue Tang
- Precision Medicine Center, Academy of Medical Science, Zhengzhou University, Zhengzhou, China.,The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| |
Collapse
|
|
15
|
Varga L, Danis D, Drsata J, Masindova I, Skopkova M, Slobodova Z, Chrobok V, Profant M, Gasperikova D. Novel variants in EDNRB gene in Waardenburg syndrome type II and SOX10 gene in PCWH syndrome. Int J Pediatr Otorhinolaryngol 2021; 140:110499. [PMID: 33234331 DOI: 10.1016/j.ijporl.2020.110499] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 11/11/2020] [Indexed: 10/23/2022]
Abstract
Waardenburg syndrome (WS) is a clinically and genetically heterogeneous group of inherited disorders manifesting with sensorineural hearing loss and pigmentary anomalies. Here we present two Caucasian families with novel variants in EDNRB and SOX10 representing both sides of phenotype spectrum in WS. The c.521G>A variant in EDNRB identified in Family 1 leads to disruption of the cysteine disulfide bridge between extracellular segments of endothelin receptor type B and causes relatively mild phenotype of WS type II with low penetrance. The novel nonsense variant c.900C>A in SOX10 detected in Family 2 leads to PCWH syndrome and was found to be lethal.
Collapse
Affiliation(s)
- Lukas Varga
- Department of Otorhinolaryngology-Head and Neck Surgery, Faculty of Medicine and University Hospital, Comenius University Bratislava, Slovakia; DIABGENE Laboratory, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
| | - Daniel Danis
- DIABGENE Laboratory, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
| | - Jakub Drsata
- Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital Hradec Kralove, Charles University, Faculty of Medicine in Hradec Kralove, Czech Republic.
| | - Ivica Masindova
- DIABGENE Laboratory, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
| | - Martina Skopkova
- DIABGENE Laboratory, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
| | - Zuzana Slobodova
- Department of Otorhinolaryngology-Head and Neck Surgery, Faculty of Medicine and University Hospital, Comenius University Bratislava, Slovakia; DIABGENE Laboratory, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
| | - Viktor Chrobok
- Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital Hradec Kralove, Charles University, Faculty of Medicine in Hradec Kralove, Czech Republic.
| | - Milan Profant
- Department of Otorhinolaryngology-Head and Neck Surgery, Faculty of Medicine and University Hospital, Comenius University Bratislava, Slovakia.
| | - Daniela Gasperikova
- DIABGENE Laboratory, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia.
| |
Collapse
|
|
16
|
Niego A, Benítez-Burraco A. Autism and Williams syndrome: Dissimilar socio-cognitive profiles with similar patterns of abnormal gene expression in the blood. AUTISM : THE INTERNATIONAL JOURNAL OF RESEARCH AND PRACTICE 2020; 25:464-489. [PMID: 33143449 DOI: 10.1177/1362361320965074] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
LAY ABSTRACT Autism spectrum disorders and Williams syndrome are complex cognitive conditions exhibiting quite opposite features in the social domain: whereas people with autism spectrum disorders are mostly hyposocial, subjects with Williams syndrome are usually reported as hypersocial. At the same time, autism spectrum disorders and Williams syndrome share some common underlying behavioral and cognitive deficits. It is not clear, however, which genes account for the attested differences (and similarities) in the socio-cognitive domain. In this article, we adopted a comparative molecular approach and looked for genes that might be differentially (or similarly) regulated in the blood of people with these conditions. We found a significant overlap between genes dysregulated in the blood of patients compared to neurotypical controls, with most of them being upregulated or, in some cases, downregulated. Still, genes with similar expression trends can exhibit quantitative differences between conditions, with most of them being more dysregulated in Williams syndrome than in autism spectrum disorders. Differentially expressed genes are involved in aspects of brain development and function (particularly dendritogenesis) and are expressed in brain areas (particularly the cerebellum, the thalamus, and the striatum) of relevance for the autism spectrum disorder and the Williams syndrome etiopathogenesis. Overall, these genes emerge as promising candidates for the similarities and differences between the autism spectrum disorder and the Williams syndrome socio-cognitive profiles.
Collapse
|
|
17
|
Reynolds K, Zhang S, Sun B, Garland M, Ji Y, Zhou CJ. Genetics and signaling mechanisms of orofacial clefts. Birth Defects Res 2020; 112:1588-1634. [PMID: 32666711 PMCID: PMC7883771 DOI: 10.1002/bdr2.1754] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 06/11/2020] [Accepted: 06/15/2020] [Indexed: 12/31/2022]
Abstract
Craniofacial development involves several complex tissue movements including several fusion processes to form the frontonasal and maxillary structures, including the upper lip and palate. Each of these movements are controlled by many different factors that are tightly regulated by several integral morphogenetic signaling pathways. Subject to both genetic and environmental influences, interruption at nearly any stage can disrupt lip, nasal, or palate fusion and result in a cleft. Here, we discuss many of the genetic risk factors that may contribute to the presentation of orofacial clefts in patients, and several of the key signaling pathways and underlying cellular mechanisms that control lip and palate formation, as identified primarily through investigating equivalent processes in animal models, are examined.
Collapse
Affiliation(s)
- Kurt Reynolds
- Department of Biochemistry and Molecular Medicine, University of California at Davis, School of Medicine, Sacramento, CA 95817
- Institute for Pediatric Regenerative Medicine of Shriners Hospitals for Children, University of California at Davis, School of Medicine, Sacramento, CA 95817
- Biochemistry, Molecular, Cellular, and Developmental Biology (BMCDB) graduate group, University of California, Davis, CA 95616
| | - Shuwen Zhang
- Department of Biochemistry and Molecular Medicine, University of California at Davis, School of Medicine, Sacramento, CA 95817
- Institute for Pediatric Regenerative Medicine of Shriners Hospitals for Children, University of California at Davis, School of Medicine, Sacramento, CA 95817
| | - Bo Sun
- Department of Biochemistry and Molecular Medicine, University of California at Davis, School of Medicine, Sacramento, CA 95817
- Institute for Pediatric Regenerative Medicine of Shriners Hospitals for Children, University of California at Davis, School of Medicine, Sacramento, CA 95817
| | - Michael Garland
- Department of Biochemistry and Molecular Medicine, University of California at Davis, School of Medicine, Sacramento, CA 95817
- Institute for Pediatric Regenerative Medicine of Shriners Hospitals for Children, University of California at Davis, School of Medicine, Sacramento, CA 95817
| | - Yu Ji
- Department of Biochemistry and Molecular Medicine, University of California at Davis, School of Medicine, Sacramento, CA 95817
- Institute for Pediatric Regenerative Medicine of Shriners Hospitals for Children, University of California at Davis, School of Medicine, Sacramento, CA 95817
- Biochemistry, Molecular, Cellular, and Developmental Biology (BMCDB) graduate group, University of California, Davis, CA 95616
| | - Chengji J. Zhou
- Department of Biochemistry and Molecular Medicine, University of California at Davis, School of Medicine, Sacramento, CA 95817
- Institute for Pediatric Regenerative Medicine of Shriners Hospitals for Children, University of California at Davis, School of Medicine, Sacramento, CA 95817
- Biochemistry, Molecular, Cellular, and Developmental Biology (BMCDB) graduate group, University of California, Davis, CA 95616
| |
Collapse
|
|
18
|
Zhang L, Wu X, Lin X. Gene therapy for genetic mutations affecting non-sensory cells in the cochlea. Hear Res 2020; 394:107858. [PMID: 31791650 DOI: 10.1016/j.heares.2019.107858] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/13/2019] [Accepted: 11/22/2019] [Indexed: 01/15/2023]
Abstract
Congenital hearing loss (HL) affects about 1 in every 500 infants. Among those affected more than half are caused by genetic mutations. According to the cellular sites affected by mutations in the cochlea, deafness genes could be classified into three major groups: those affecting the function of hair cells and synapses, cochlear supporting cells, and cells in the stria vascularis (SV) as well as in the lateral wall. The second and third groups account for more than half of all sensorineural hearing loss (SNHL) cases caused by genetic mutations. Current major treatment options for SNHL patients are hearing aids and cochlear implants (CIs). Hearing aids can only help patients with moderate to severe HL. Resolution of CIs is still improving and these devices are quite expensive especially when lifetime rehabilitation and maintenance costs are included. Tremendous efforts have been made to find novel treatments that are expected to restore hearing with higher-resolution and more natural quality, and to have a significantly lower cost over the lifetime of uses. Gene therapy studies have made impressive progresses in preclinical trials. This review focuses on deafness genes that affect supporting cells and cells in the SV of the cochlea. We will discuss recent progresses and remaining challenges for gene therapies targeting mutations in deafness genes belonging to this category.
Collapse
Affiliation(s)
- Li Zhang
- Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Department of Otolaryngology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322-3030, USA
| | - Xuewen Wu
- Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital of Central South University, 87 Xiangya Road, Changsha, Hunan, 410008, China; Department of Otolaryngology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322-3030, USA
| | - Xi Lin
- Department of Otolaryngology, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322-3030, USA.
| |
Collapse
|
|
19
|
Li S, Guo M, Ruan B, Liu Y, Cui X, Han W, Li R. A Novel PAX3 Mutation in a Chinese Family with Waardenburg Syndrome Type 1. Genet Test Mol Biomarkers 2020; 24:249-255. [PMID: 32250160 DOI: 10.1089/gtmb.2019.0231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Aims: To determine the clinical characteristics and genetic cause of Waardenburg syndrome type 1 (WS1) in a Chinese family. Materials and Methods: Evaluations, including history, clinical features, and audiological tests, were performed on the proband and her parents. Genetic analyses were performed targeting 144 known deafness genes using a next-generation sequencing panel. Bioinformatic analyses were used to analyze the candidate mutation. Results: The proband and her parents suffered from congenital bilateral profound hearing loss. Her mother exhibited bilateral blue irides. WS1 was diagnosed in the proband and her mother according to the Waardenburg syndrome consortium criteria: the calculated W index of the proband was 2.39 and that of her mother was 2.31. A novel mutation c.1076_1077del (p.Thr359fs) in exon 7 of the PAX3 gene (paired box 3) was identified in the proband and her mother that was absent in the father and controls. Conclusion: Mutations in exon 7 of the PAX3 gene are rare. We identified a novel frameshift mutation in exon 7 of the PAX3 gene that we determined was responsible for WS1 in this family.
Collapse
Affiliation(s)
- Shuling Li
- Department of Otolaryngology, 1st Affiliated Hospital of Kunming Medical University, Kunning, China
| | - Min Guo
- Department of Otolaryngology, 1st Affiliated Hospital of Kunming Medical University, Kunning, China
| | - Biao Ruan
- Department of Otolaryngology, 1st Affiliated Hospital of Kunming Medical University, Kunning, China
| | - Ya Liu
- Department of Otolaryngology, 1st Affiliated Hospital of Kunming Medical University, Kunning, China
| | - Xin Cui
- Department of Otolaryngology, 1st Affiliated Hospital of Kunming Medical University, Kunning, China
| | - Weiwei Han
- Department of Otolaryngology, 1st Affiliated Hospital of Kunming Medical University, Kunning, China
| | - Ruomei Li
- Department of Otolaryngology, 1st Affiliated Hospital of Kunming Medical University, Kunning, China
| |
Collapse
|
|
20
|
Gaczkowska A, Biedziak B, Budner M, Zadurska M, Lasota A, Hozyasz KK, Dąbrowska J, Wójcicki P, Szponar-Żurowska A, Żukowski K, Jagodziński PP, Mostowska A. PAX7 nucleotide variants and the risk of non-syndromic orofacial clefts in the Polish population. Oral Dis 2019; 25:1608-1618. [PMID: 31173442 DOI: 10.1111/odi.13139] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 05/16/2019] [Accepted: 06/03/2019] [Indexed: 12/12/2022]
Abstract
OBJECTIVE The etiology of non-syndromic cleft lip with or without cleft palate (nsCL/P) is multifactorial, heterogeneous, and still not completely understood. The aim of the present study was to examine the associations between common and rare PAX7 nucleotide variants and the risk of this common congenital anomaly in a Polish population. SUBJECTS AND METHODS Eight top nsCL/P-associated PAX7 variants identified in our cleft genome-wide association study (GWAS) were selected for replication analysis in an independent group of patients and controls (n = 247 and n = 445, respectively). In addition, mutation screening of the PAX7 protein-coding region was conducted. RESULTS Analysis of the pooled data from the GWAS and replication study confirmed that common PAX7 nucleotide variants are significantly associated with the increased risk of nsCL/P. The strongest individual variant was rs1339062 (c.586 + 15617T > C) with a p-value = 2.47E-05 (OR = 1.4, 95%CI: 1.20-1.64). Sequencing analysis identified a novel synonymous PAX7 substitution (c.87G > A, p.Val29Val) in a single patient with nsCLP. This transition located in the early exonic position was predicted to disrupt potential splice enhancer elements. CONCLUSION Our study confirmed that PAX7 is a strong candidate gene for nsCL/P. Nucleotide variants of this gene contribute to the etiology of nsCL/P in the homogenous Polish population.
Collapse
Affiliation(s)
- Agnieszka Gaczkowska
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, Poland
| | - Barbara Biedziak
- Clinic of Craniofacial Anomalies, Poznan University of Medical Sciences, Poznan, Poland
| | - Margareta Budner
- Eastern Poland Burn Treatment and Reconstructive Center, Leczna, Poland
| | | | - Agnieszka Lasota
- Department of Jaw Orthopedics, Medical University of Lublin, Lublin, Poland
| | - Kamil K Hozyasz
- Institute of Health Sciences, State School of Higher Education, Biala Podlaska, Poland
| | - Justyna Dąbrowska
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, Poland
| | - Piotr Wójcicki
- Plastic Surgery Clinic, Medical University in Wroclaw, Wroclaw, Poland
| | - Anna Szponar-Żurowska
- Clinic of Craniofacial Anomalies, Poznan University of Medical Sciences, Poznan, Poland
| | - Kacper Żukowski
- Department of Cattle Breeding, National Research Institute of Animal Production, Balice, Poland
| | - Paweł P Jagodziński
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, Poland
| | - Adrianna Mostowska
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, Poland
| |
Collapse
|
|
21
|
Ma J, Lin K, Jiang HC, Yang Y, Zhang Y, Yang G, Sun H, Ming C, Bi X, Zhang T, Ruan B. A novel mutation of the PAX3 gene in a Chinese family with Waardenburg syndrome type I. Mol Genet Genomic Med 2019; 7:e00798. [PMID: 31190477 PMCID: PMC6625151 DOI: 10.1002/mgg3.798] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 05/15/2019] [Accepted: 05/17/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND To analyze the clinical phenotypes and genetic variants of a Chinese family with Waardenburg syndrome (WS) and to explore the possible molecular pathogenesis of WS. METHODS The clinical data from a patient and his family were collected. The genomic DNA of the patient and his family was purified from their peripheral blood. All exons and flanking sequences of the MITF, PAX3, SOX10, SNAI2, END3, and EDNRB genes were investigated through high-throughput sequencing. Based on the results of high-throughput sequencing, genetic variants in the patient and his family were verified and analyzed by Sanger sequencing. RESULTS The patient was diagnosed with typical WS1 that manifested in hearing impairment, inner canthus ectopia and heterochromic iris. Sanger sequencing revealed the pathogenic heterozygous c.420-424de1CGCGGinsTTAC mutation in the PAX3 gene in the proband, which is a frameshift mutation that changed the amino acid sequence of the PAX3 protein from AVCDRNTVPSV to YSVIETPCRQ* (* refers to a stop codon) from amino acids 141-151. The stop codon induced by this mutation resulted in the truncation of the PAX3 protein. The same mutation sites were also found in the mother and younger sister of the proband. No previous report of this mutation was found in the Human Gene Mutation Database. CONCLUSION The novel heterozygous c.420-424de1CGCGGinsTTAC mutation is the molecular pathological cause for WS1 in our patient. The clinical and genetic characterization of this family with WS1 elucidated the genetic heterogeneity of PAX3 in WS1. Moreover, the mutation detected in this case has expanded the database of PAX3 mutations.
Collapse
Affiliation(s)
- Jing Ma
- Department of Otolaryngology, Head & Neck Surgery, Kunming Children's Hospital, Kunming, China
| | - Ken Lin
- Department of Otolaryngology, Head & Neck Surgery, Kunming Children's Hospital, Kunming, China
| | - Hong-Chao Jiang
- Yunnan Pediatric Institute, Kunming Children's Hospital, Kunming, China
| | - Yanli Yang
- Department of Otolaryngology, First Hospital of Kunming Medical University, Kunming, China
| | - Yu Zhang
- Yunnan Pediatric Institute, Kunming Children's Hospital, Kunming, China
| | - Guilian Yang
- Yunnan Rehabilitation School For Children With Hearing Impairment, Kunming, China
| | - Hao Sun
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union of Medical College, Kunming, China
| | - Cheng Ming
- Department of Otolaryngology, Head & Neck Surgery, Kunming Children's Hospital, Kunming, China
| | - Xianyun Bi
- Department of Otolaryngology, Head & Neck Surgery, Kunming Children's Hospital, Kunming, China
| | - Tiesong Zhang
- Department of Otolaryngology, Head & Neck Surgery, Kunming Children's Hospital, Kunming, China
| | - Biao Ruan
- Department of Otolaryngology, First Hospital of Kunming Medical University, Kunming, China
| |
Collapse
|
|
22
|
Schneider M, Rother S, Möller S, Schnabelrauch M, Scharnweber D, Simon J, Hintze V, Savkovic V. Sulfated hyaluronan‐containing artificial extracellular matrices promote proliferation of keratinocytes and melanotic phenotype of melanocytes from the outer root sheath of hair follicles. J Biomed Mater Res A 2019; 107:1640-1653. [DOI: 10.1002/jbm.a.36680] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 01/18/2019] [Accepted: 03/13/2019] [Indexed: 12/18/2022]
Affiliation(s)
- Marie Schneider
- Saxon Incubator for Clinical TranslationLeipzig University TRR 67, Leipzig Germany
| | - Sandra Rother
- Max Bergmann Center of BiomaterialsInstitute of Materials Science, TU Dresden TRR 67, Dresden Germany
| | | | | | - Dieter Scharnweber
- Max Bergmann Center of BiomaterialsInstitute of Materials Science, TU Dresden TRR 67, Dresden Germany
| | - Jan‐Christoph Simon
- Clinic for Dermatology, Venerology and AllergologyFaculty of Medicine, Leipzig University Clinic TRR 67, Leipzig Germany
| | - Vera Hintze
- Max Bergmann Center of BiomaterialsInstitute of Materials Science, TU Dresden TRR 67, Dresden Germany
| | - Vuk Savkovic
- Saxon Incubator for Clinical TranslationLeipzig University TRR 67, Leipzig Germany
| |
Collapse
|
|
23
|
Benítez-Burraco A, Kimura R. Robust Candidates for Language Development and Evolution Are Significantly Dysregulated in the Blood of People With Williams Syndrome. Front Neurosci 2019; 13:258. [PMID: 30971880 PMCID: PMC6444191 DOI: 10.3389/fnins.2019.00258] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 03/05/2019] [Indexed: 01/06/2023] Open
Abstract
Williams syndrome (WS) is a clinical condition, involving cognitive deficits and an uneven language profile, which has been the object of intense inquiry over the last decades. Although WS results from the hemideletion of around two dozen genes in chromosome 7, no gene has yet been probed to account for, or contribute significantly to, the language problems exhibited by the affected people. In this paper we have relied on gene expression profiles in the peripheral blood of WS patients obtained by microarray analysis and show that several robust candidates for language disorders and/or for language evolution in the species, all of them located outside the hemideleted region, are up- or downregulated in the blood of subjects with WS. Most of these genes play a role in the development and function of brain areas involved in language processing, which exhibit structural and functional anomalies in people with this condition. Overall, these genes emerge as robust candidates for language dysfunction in WS.
Collapse
Affiliation(s)
- Antonio Benítez-Burraco
- Department of Spanish, Linguistics, and Theory of Literature (Linguistics), Faculty of Philology, University of Seville, Seville, Spain
| | - Ryo Kimura
- Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| |
Collapse
|
|
24
|
Niego A, Benítez-Burraco A. Williams Syndrome, Human Self-Domestication, and Language Evolution. Front Psychol 2019; 10:521. [PMID: 30936846 PMCID: PMC6431629 DOI: 10.3389/fpsyg.2019.00521] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 02/22/2019] [Indexed: 01/06/2023] Open
Abstract
Language evolution resulted from changes in our biology, behavior, and culture. One source of these changes might be human self-domestication. Williams syndrome (WS) is a clinical condition with a clearly defined genetic basis which results in a distinctive behavioral and cognitive profile, including enhanced sociability. In this paper we show evidence that the WS phenotype can be satisfactorily construed as a hyper-domesticated human phenotype, plausibly resulting from the effect of the WS hemideletion on selected candidates for domestication and neural crest (NC) function. Specifically, we show that genes involved in animal domestication and NC development and function are significantly dysregulated in the blood of subjects with WS. We also discuss the consequences of this link between domestication and WS for our current understanding of language evolution.
Collapse
Affiliation(s)
- Amy Niego
- Ph.D. Program, Faculty of Humanities, University of Huelva, Huelva, Spain
| | - Antonio Benítez-Burraco
- Department of Spanish, Linguistics, and Theory of Literature, Faculty of Philology, University of Seville, Seville, Spain
| |
Collapse
|
|
25
|
Lajis AFB, Ariff AB. Discovery of new depigmenting compounds and their efficacy to treat hyperpigmentation: Evidence from in vitro study. J Cosmet Dermatol 2019; 18:703-727. [PMID: 30866156 DOI: 10.1111/jocd.12900] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Accepted: 01/22/2019] [Indexed: 12/19/2022]
Abstract
Human skin pigmentation is a result of constitutive and facultative pigmentation. Facultative pigmentation is frequently stimulated by UV radiation, pharmacologic drugs, and hormones whereby leads to the development of abnormal skin hyperpigmentation. To date, many state-of-art depigmenting compounds have been studied using in vitro model to treat hyperpigmentation problems for cosmetic dermatological applications; little attention has been made to compare the effectiveness of these depigmenting compounds and their mode of actions. In this present article, new and recent depigmenting compounds, their melanogenic pathway targets, and modes of action are reviewed. This article compares the effectiveness of these new depigmenting compounds to modulate several melanogenesis-regulatory enzymes and proteins such as tyrosinase (TYR), TYR-related protein-1 (TRP1), TYR-related protein-2 (TRP2), microphthalmia-associated transcription factor (MITF), extracellular signal-regulated kinase (ERK) and N-terminal kinases (JNK) and mitogen-activated protein kinase p38 (p38 MAPK). Other evidences from in vitro assays such as inhibition on melanosomal transfer, proteasomes, nitric oxide, and inflammation-induced melanogenesis are also highlighted. This article also reviews analytical techniques in different assays performed using in vitro model as well as their advantages and limitations. This article also provides an insight on recent finding and re-examination of some protocols as well as their effectiveness and reliability in the evaluation of depigmenting compounds. Evidence and support from related patents are also incorporated in this present article to give an overview on current patented technology, latest trends, and intellectual values of some depigmenting compounds and protocols, which are rarely highlighted in the literatures.
Collapse
Affiliation(s)
- Ahmad Firdaus B Lajis
- Department of Bioprocess Technology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Malaysia.,Bioprocessing and Biomanufacturing Research Center, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Malaysia.,Institute of Bioscience, Universiti Putra Malaysia, Serdang, Malaysia
| | - Arbakariya B Ariff
- Department of Bioprocess Technology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Malaysia.,Bioprocessing and Biomanufacturing Research Center, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang, Malaysia
| |
Collapse
|
|
26
|
Ritter KE, Martin DM. Neural crest contributions to the ear: Implications for congenital hearing disorders. Hear Res 2018; 376:22-32. [PMID: 30455064 DOI: 10.1016/j.heares.2018.11.005] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 10/30/2018] [Accepted: 11/12/2018] [Indexed: 12/16/2022]
Abstract
Congenital hearing disorders affect millions of children worldwide and can significantly impact acquisition of speech and language. Efforts to identify the developmental genetic etiologies of conductive and sensorineural hearing losses have revealed critical roles for cranial neural crest cells (NCCs) in ear development. Cranial NCCs contribute to all portions of the ear, and defects in neural crest development can lead to neurocristopathies associated with profound hearing loss. The molecular mechanisms governing the development of neural crest derivatives within the ear are partially understood, but many questions remain. In this review, we describe recent advancements in determining neural crest contributions to the ear, how they inform our understanding of neurocristopathies, and highlight new avenues for further research using bioinformatic approaches.
Collapse
Affiliation(s)
- K Elaine Ritter
- Department of Pediatrics, The University of Michigan Medical School, Ann Arbor, MI, USA
| | - Donna M Martin
- Department of Pediatrics, The University of Michigan Medical School, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
| |
Collapse
|
|
27
|
DiStefano MT, Hemphill SE, Cushman BJ, Bowser MJ, Hynes E, Grant AR, Siegert RK, Oza AM, Gonzalez MA, Amr SS, Rehm HL, Abou Tayoun AN. Curating Clinically Relevant Transcripts for the Interpretation of Sequence Variants. J Mol Diagn 2018; 20:789-801. [PMID: 30096381 PMCID: PMC6204605 DOI: 10.1016/j.jmoldx.2018.06.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Revised: 05/20/2018] [Accepted: 06/19/2018] [Indexed: 10/28/2022] Open
Abstract
Variant interpretation depends on accurate annotations using biologically relevant transcripts. We have developed a systematic strategy for designating primary transcripts and have applied it to 109 hearing loss-associated genes that were divided into three categories. Category 1 genes (n = 38) had a single transcript; category 2 genes (n = 33) had multiple transcripts, but a single transcript was sufficient to represent all exons; and category 3 genes (n = 38) had multiple transcripts with unique exons. Transcripts were curated with respect to gene expression reported in the literature and the Genotype-Tissue Expression Project. In addition, high-frequency loss-of-function variants in the Genome Aggregation Database and disease-causing variants in ClinVar and the Human Gene Mutation Database across the 109 genes were queried. These data were used to classify exons as clinically significant, insignificant, or of uncertain significance. Interestingly, 6% of all exons, containing 124 reportedly disease-causing variants, were of uncertain significance. Finally, we used exon-level next-generation sequencing quality metrics generated at two clinical laboratories and identified a total of 43 technically challenging exons in 20 different genes that had inadequate coverage and/or homology issues that might lead to false-variant calls. We have demonstrated that transcript analysis plays a critical role in accurate clinical variant interpretation.
Collapse
Affiliation(s)
- Marina T DiStefano
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts
| | - Sarah E Hemphill
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts
| | - Brandon J Cushman
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts
| | - Mark J Bowser
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts
| | - Elizabeth Hynes
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts
| | - Andrew R Grant
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts
| | - Rebecca K Siegert
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts
| | - Andrea M Oza
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts
| | - Michael A Gonzalez
- Division of Genomic Diagnostics, The Children's Hospital of Philadelphia, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Sami S Amr
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts; Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Heidi L Rehm
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Department of Medical and Population Genetics, The Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts
| | - Ahmad N Abou Tayoun
- Division of Genomic Diagnostics, The Children's Hospital of Philadelphia, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Genetics Department, Al Jalila Children's Specialty Hospital, Dubai, United Arab Emirates.
| |
Collapse
|
|
28
|
PAX3: A Molecule with Oncogenic or Tumor Suppressor Function Is Involved in Cancer. BIOMED RESEARCH INTERNATIONAL 2018. [DOI: 10.1155/2018/1095459] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Metastasis is the most deadly aspect of cancer and results from acquired gene regulation abnormalities in tumor cells. Transcriptional regulation is an essential component of controlling of gene function and its failure could contribute to tumor progression and metastasis. During cancer progression, deregulation of oncogenic or tumor suppressive transcription factors, as well as master cell fate regulators, collectively influences multiple steps of the metastasis cascade, including local invasion and dissemination of the tumor to distant organs. Transcription factor PAX3/Pax3, which contributes to diverse cell lineages during embryonic development, plays a major role in tumorigenesis. Mutations in this gene can cause neurodevelopmental disease and the existing literature supports that there is a potential link between aberrant expression of PAX3 genes in adult tissues and a wide variety of cancers. PAX3 function is tissue-specific and could contribute to tumorigenesis either directly as oncogene or as a tumor suppressor by losing its function. In this review, we discuss comprehensively the differential role played by PAX3 in various tissues and how its aberrant expression is implicated in disease development. This review particularly highlights the oncogenic and tumor suppressor role played by PAX3 in different cancers and underlines the importance of precisely identifying tissue-specific role of PAX3 in order to determine its exact role in development of cancer.
Collapse
|
|
29
|
Lee DH, Ahn SS, Kim JB, Lim Y, Lee YH, Shin SY. Downregulation of α-Melanocyte-Stimulating Hormone-Induced Activation of the Pax3-MITF-Tyrosinase Axis by Sorghum Ethanolic Extract in B16F10 Melanoma Cells. Int J Mol Sci 2018; 19:ijms19061640. [PMID: 29865165 PMCID: PMC6032395 DOI: 10.3390/ijms19061640] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 05/25/2018] [Accepted: 05/30/2018] [Indexed: 01/15/2023] Open
Abstract
Ultraviolet irradiation-induced hyperpigmentation of the skin is associated with excessive melanin production in melanocytes. Tyrosinase (TYR) is a key enzyme catalyzing the rate-limiting step in melanogenesis. TYR expression is controlled by microphthalmia-associated transcription factor (MITF) expression. Sorghum is a cereal crop widely used in a variety of foods worldwide. Sorghum contains many bioactive compounds and is beneficial to human health. However, the effects of sorghum in anti-melanogenesis have not been well characterized. In this study, the biological activity of sorghum ethanolic extract (SEE) on α-melanocyte-stimulating hormone (α-MSH)-induced TYR expression was evaluated in B16F10 melanoma cells. SEE attenuated α-MSH-induced TYR gene promoter activity through the downregulation of the transcription factor MITF. We found that paired box gene 3 (Pax3) contributes to the maximal induction of MITF gene promoter activity. Further analysis demonstrated that SEE inhibited α-MSH-induced Pax3 expression. The collective results indicate that SEE attenuates α-MSH-induced TYR expression through the suppression of Pax3-mediated MITF gene promoter activity. Targeting the Pax3-MITF axis pathway could be considered a potential strategy to increase the efficacy of anti-melanogenesis.
Collapse
Affiliation(s)
- Da Hyun Lee
- Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, Seoul 05029, Korea.
| | - Sung Shin Ahn
- Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, Seoul 05029, Korea.
| | - Jung-Bong Kim
- Functional Food and Nutrition Division, National Institute of Agricultural Sciences, Rural Development Administration, Jeonju 55365, Korea.
| | - Yoongho Lim
- Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul 05029, Korea.
| | - Young Han Lee
- Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, Seoul 05029, Korea.
- Cancer and Metabolism Institute, Konkuk University, Seoul 05029, Korea.
| | - Soon Young Shin
- Department of Biological Sciences, Sanghuh College of Life Sciences, Konkuk University, Seoul 05029, Korea.
- Cancer and Metabolism Institute, Konkuk University, Seoul 05029, Korea.
| |
Collapse
|
|
30
|
Gettelfinger JD, Dahl JP. Syndromic Hearing Loss: A Brief Review of Common Presentations and Genetics. J Pediatr Genet 2018; 7:1-8. [PMID: 29441214 PMCID: PMC5809162 DOI: 10.1055/s-0037-1617454] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 11/29/2017] [Indexed: 02/07/2023]
Abstract
Congenital hearing loss is one of the most common birth defects worldwide, with around 1 in 500 people experiencing some form of severe hearing loss. While over 400 different syndromes involving hearing loss have been described, it is important to be familiar with a wide range of syndromes involving hearing loss so an early diagnosis can be made and early intervention can be pursued to maximize functional hearing and speech-language development in the setting of verbal communication. This review aims to describe the presentation and genetics for some of the most frequently occurring syndromes involving hearing loss, including neurofibromatosis type 2, branchio-oto-renal syndrome, Treacher Collins syndrome, Stickler syndrome, Waardenburg syndrome, Pendred syndrome, Jervell and Lange-Nielsen syndrome, Usher syndromes, Refsum disease, Alport syndrome, MELAS, and MERRF.
Collapse
Affiliation(s)
- John D. Gettelfinger
- Department of Otolaryngology – Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, Indiana, United States
| | - John P. Dahl
- Department of Otolaryngology – Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, Indiana, United States
| |
Collapse
|
|
31
|
Marathe HG, Watkins-Chow DE, Weider M, Hoffmann A, Mehta G, Trivedi A, Aras S, Basuroy T, Mehrotra A, Bennett DC, Wegner M, Pavan WJ, de la Serna IL. BRG1 interacts with SOX10 to establish the melanocyte lineage and to promote differentiation. Nucleic Acids Res 2017; 45:6442-6458. [PMID: 28431046 PMCID: PMC5499657 DOI: 10.1093/nar/gkx259] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 04/04/2017] [Indexed: 12/30/2022] Open
Abstract
Mutations in SOX10 cause neurocristopathies which display varying degrees of hypopigmentation. Using a sensitized mutagenesis screen, we identified Smarca4 as a modifier gene that exacerbates the phenotypic severity of Sox10 haplo-insufficient mice. Conditional deletion of Smarca4 in SOX10 expressing cells resulted in reduced numbers of cranial and ventral trunk melanoblasts. To define the requirement for the Smarca4 -encoded BRG1 subunit of the SWI/SNF chromatin remodeling complex, we employed in vitro models of melanocyte differentiation in which induction of melanocyte-specific gene expression is closely linked to chromatin alterations. We found that BRG1 was required for expression of Dct, Tyrp1 and Tyr, genes that are regulated by SOX10 and MITF and for chromatin remodeling at distal and proximal regulatory sites. SOX10 was found to physically interact with BRG1 in differentiating melanocytes and binding of SOX10 to the Tyrp1 distal enhancer temporally coincided with recruitment of BRG1. Our data show that SOX10 cooperates with MITF to facilitate BRG1 binding to distal enhancers of melanocyte-specific genes. Thus, BRG1 is a SOX10 co-activator, required to establish the melanocyte lineage and promote expression of genes important for melanocyte function.
Collapse
Affiliation(s)
- Himangi G Marathe
- Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine and Life Sciences, 3035 Arlington Ave, Toledo, OH 43614, USA
| | - Dawn E Watkins-Chow
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-4472, USA
| | - Matthias Weider
- Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Alana Hoffmann
- Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Gaurav Mehta
- Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine and Life Sciences, 3035 Arlington Ave, Toledo, OH 43614, USA
| | - Archit Trivedi
- Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine and Life Sciences, 3035 Arlington Ave, Toledo, OH 43614, USA
| | - Shweta Aras
- Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine and Life Sciences, 3035 Arlington Ave, Toledo, OH 43614, USA
| | - Tupa Basuroy
- Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine and Life Sciences, 3035 Arlington Ave, Toledo, OH 43614, USA
| | - Aanchal Mehrotra
- Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine and Life Sciences, 3035 Arlington Ave, Toledo, OH 43614, USA
| | - Dorothy C Bennett
- Molecular and Clinical Sciences Research Institute, St George's, University of London, London SW17 0RE, UK
| | - Michael Wegner
- Institut für Biochemie, Emil-Fischer-Zentrum, Friedrich-Alexander Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - William J Pavan
- National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-4472, USA
| | - Ivana L de la Serna
- Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine and Life Sciences, 3035 Arlington Ave, Toledo, OH 43614, USA
| |
Collapse
|
|
32
|
Proskorovski-Ohayon R, Kadir R, Michalowski A, Flusser H, Perez Y, Hershkovitz E, Sivan S, Birk OS. PAX7mutation in a syndrome of failure to thrive, hypotonia, and global neurodevelopmental delay. Hum Mutat 2017; 38:1671-1683. [DOI: 10.1002/humu.23310] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 07/16/2017] [Accepted: 07/27/2017] [Indexed: 11/11/2022]
Affiliation(s)
- Regina Proskorovski-Ohayon
- The Morris Kahn Laboratory of Human Genetics; National Institute for Biotechnology in the Negev and Faculty of Health Sciences; Ben Gurion University of the Negev; Beer Sheva Israel
| | - Rotem Kadir
- The Morris Kahn Laboratory of Human Genetics; National Institute for Biotechnology in the Negev and Faculty of Health Sciences; Ben Gurion University of the Negev; Beer Sheva Israel
| | - Analia Michalowski
- Zussman Child Development Center; Division of Pediatrics; Soroka University Medical Center; Faculty of Health Sciences; Ben Gurion University of the Negev; Beer Sheva Israel
| | - Hagit Flusser
- Zussman Child Development Center; Division of Pediatrics; Soroka University Medical Center; Faculty of Health Sciences; Ben Gurion University of the Negev; Beer Sheva Israel
| | - Yonatan Perez
- The Morris Kahn Laboratory of Human Genetics; National Institute for Biotechnology in the Negev and Faculty of Health Sciences; Ben Gurion University of the Negev; Beer Sheva Israel
| | - Eli Hershkovitz
- Pediatric Endocrinology and Metabolism Unit; Division of Pediatrics; Soroka University Medical Center; Faculty of Health Sciences; Ben Gurion University of the Negev; Beer Sheva Israel
| | - Sara Sivan
- The Morris Kahn Laboratory of Human Genetics; National Institute for Biotechnology in the Negev and Faculty of Health Sciences; Ben Gurion University of the Negev; Beer Sheva Israel
| | - Ohad S. Birk
- The Morris Kahn Laboratory of Human Genetics; National Institute for Biotechnology in the Negev and Faculty of Health Sciences; Ben Gurion University of the Negev; Beer Sheva Israel
- Genetics Institute; Soroka University Medical Center; affiliated to Ben Gurion University of the Negev; Beer Sheva Israel
| |
Collapse
|
|
33
|
Gong HM, Wang J, Xu J, Zhou ZY, Li JW, Chen SF. Identification of rare paired box 3 variant in strabismus by whole exome sequencing. Int J Ophthalmol 2017; 10:1223-1228. [PMID: 28861346 DOI: 10.18240/ijo.2017.08.06] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 04/24/2017] [Indexed: 11/23/2022] Open
Abstract
AIM To identify the potentially pathogenic gene variants that contributes to the etiology of strabismus. METHODS A Chinese pedigree with strabismus was collected and the exomes of two affected individuals were sequenced using the next-generation sequencing technology. The resulting variants from exome sequencing were filtered by subsequent bioinformatics methods and the candidate mutation was verified as heterozygous in the affected proposita and her mother by sanger sequencing. RESULTS Whole exome sequencing and filtering identified a nonsynonymous mutation c.434G-T transition in paired box 3 (PAX3) in the two affected individuals, which were predicted to be deleterious by more than 4 bioinformatics programs. This altered amino acid residue was located in the conserved PAX domain of PAX3. This gene encodes a member of the PAX family of transcription factors, which play critical roles during fetal development. Mutations in PAX3 were associated with Waardenburg syndrome with strabismus. CONCLUSION Our results report that the c.434G-T mutation (p.R145L) in PAX3 may contribute to strabismus, expanding our understanding of the causally relevant genes for this disorder.
Collapse
Affiliation(s)
- Hui-Min Gong
- Ophthalmologic Center, Qingdao Municipal Hospital, the Affiliated Municipal Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Jing Wang
- Department of Ophthalmology, Dezhou People's Hospital, Dezhou 253000, Shandong Province, China
| | - Jing Xu
- Department of Ophthalmology, Weifang People's Hospital, Weifang 261041, Shandong Province, China
| | - Zhan-Yu Zhou
- Ophthalmologic Center, Qingdao Municipal Hospital, the Affiliated Municipal Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Jing-Wen Li
- Ophthalmologic Center, Qingdao Municipal Hospital, the Affiliated Municipal Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Shu-Fang Chen
- Department of Medical Equipment, Weifang People's Hospital, Weifang 261041, Shandong Province, China
| |
Collapse
|
|
34
|
Haynes P, Kernan K, Zhou SL, Miller DG. Expression patterns of FSHD-causing DUX4 and myogenic transcription factors PAX3 and PAX7 are spatially distinct in differentiating human stem cell cultures. Skelet Muscle 2017. [PMID: 28637492 PMCID: PMC5480156 DOI: 10.1186/s13395-017-0130-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Background Facioscapulohumeral muscular dystrophy (FSHD) is most commonly inherited in an autosomal dominant pattern and caused by the abnormal expression of DUX4 in skeletal muscle. The DUX4 transcription factor has DNA binding domains similar to several paired class homeotic transcription factors, but only myogenic factors PAX3 and PAX7 rescue cell viability when co-expressed with DUX4 in mouse myoblasts. This observation suggests competition for DNA binding sites in satellite cells might limit muscle repair and may be one aspect of DUX4-associated myotoxicity. The competition hypothesis requires that DUX4 and PAX3/7 be expressed in the same cells at some point during development or in adult tissues. We modeled myogenesis using human isogenic iPS and ES cells and examined expression patterns of DUX4, PAX3, and PAX7 to determine if conditions that promote PAX3 and PAX7 expression in cell culture also promote DUX4 expression in the same cells. Methods Isogenic iPSCs were generated from human fibroblasts of two FSHD-affected individuals with somatic mosaicism. Clones containing the shortened FSHD-causing D4Z4 array or the long non-pathogenic array were isolated from the same individuals. We also examined myogenesis in commercially available hES cell lines derived from FSHD-affected and non-affected embryos. DUX4, PAX3, and PAX7 messenger RNAs (mRNAs) were quantified during a 40-day differentiation protocol, and antibodies were used to identify cell types in different stages of differentiation to determine if DUX4 and PAX3 or PAX7 are present in the same cells. Results Human iPS and ES cells differentiated into skeletal myocytes as evidenced by Titin positive multinucleated fibers appearing toward the end of a 40-day differentiation protocol. PAX3 and PAX7 were expressed at similar times during differentiation, and DUX4 positive nuclei were seen at terminal stages of differentiation in cells containing the short D4Z4 arrays. Nuclei that expressed both DUX4 and PAX3, or DUX4 and PAX7 were not observed after examining immunostained nuclei at five different time points during myogenic differentiation of pluripotent cells. Conclusions We conclude that DUX4, PAX3, and PAX7 have distinct expression patterns during myogenic differentiation of stem cells. Our findings are consistent with the hypothesis that muscle damage in FSHD is due to DUX4-mediated toxicity causing destruction of terminally differentiated myofibers. While these studies examine DUX4, PAX3, and PAX7 expression patterns during stem cell myogenesis, they should not be generalized to tissue repair in adult muscle tissue. Electronic supplementary material The online version of this article (doi:10.1186/s13395-017-0130-1) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Premi Haynes
- Division of Genetic Medicine, Department of Pediatrics, University of Washington, Campus Box 358056, 850 Republican Street, Room N416, Seattle, WA, 98109, USA
| | - Kelly Kernan
- Division of Genetic Medicine, Department of Pediatrics, University of Washington, Campus Box 358056, 850 Republican Street, Room N416, Seattle, WA, 98109, USA
| | - Suk-Lin Zhou
- Division of Genetic Medicine, Department of Pediatrics, University of Washington, Campus Box 358056, 850 Republican Street, Room N416, Seattle, WA, 98109, USA
| | - Daniel G Miller
- Division of Genetic Medicine, Department of Pediatrics, University of Washington, Campus Box 358056, 850 Republican Street, Room N416, Seattle, WA, 98109, USA.
| |
Collapse
|
|
35
|
Issa S, Bondurand N, Faubert E, Poisson S, Lecerf L, Nitschke P, Deggouj N, Loundon N, Jonard L, David A, Sznajer Y, Blanchet P, Marlin S, Pingault V. EDNRB mutations cause Waardenburg syndrome type II in the heterozygous state. Hum Mutat 2017; 38:581-593. [PMID: 28236341 DOI: 10.1002/humu.23206] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 02/02/2017] [Accepted: 02/18/2017] [Indexed: 01/21/2023]
Abstract
Waardenburg syndrome (WS) is a genetic disorder characterized by sensorineural hearing loss and pigmentation anomalies. The clinical definition of four WS types is based on additional features due to defects in structures mostly arising from the neural crest, with type I and type II being the most frequent. While type I is tightly associated to PAX3 mutations, WS type II (WS2) remains partly enigmatic with mutations in known genes (MITF, SOX10) accounting for only 30% of the cases. We performed exome sequencing in a WS2 index case and identified a heterozygous missense variation in EDNRB. Interestingly, homozygous (and very rare heterozygous) EDNRB mutations are already described in type IV WS (i.e., in association with Hirschsprung disease [HD]) and heterozygous mutations in isolated HD. Screening of a WS2 cohort led to the identification of an overall of six heterozygous EDNRB variations. Clinical phenotypes, pedigrees and molecular segregation investigations unraveled a dominant mode of inheritance with incomplete penetrance. In parallel, cellular and functional studies showed that each of the mutations impairs the subcellular localization of the receptor or induces a defective downstream signaling pathway. Based on our results, we now estimate EDNRB mutations to be responsible for 5%-6% of WS2.
Collapse
Affiliation(s)
- Sarah Issa
- INSERM U955, IMRB, Equipe 6, Créteil, France.,Université Paris 12, Faculté de Médecine, Créteil, France.,INSERM U1163, Institut IMAGINE, Equipe Embryologie et Génétique des Malformations Humaines, Paris, France
| | - Nadege Bondurand
- INSERM U955, IMRB, Equipe 6, Créteil, France.,Université Paris 12, Faculté de Médecine, Créteil, France.,INSERM U1163, Institut IMAGINE, Equipe Embryologie et Génétique des Malformations Humaines, Paris, France
| | - Emmanuelle Faubert
- AP-HP, Groupe Henri Mondor-Albert Chenevier, Département de Génétique, Créteil, France
| | - Sylvain Poisson
- AP-HP, Hôpital Necker, Laboratoire de Génétique Moléculaire, Paris, France
| | - Laure Lecerf
- INSERM U955, IMRB, Equipe 6, Créteil, France.,Université Paris 12, Faculté de Médecine, Créteil, France
| | | | - Naima Deggouj
- ENT Department and Audio-Phonological Center, Cliniques universitaires St Luc, Université catholique de Louvain, Brussels, Belgium
| | | | - Laurence Jonard
- AP-HP, Hôpital Necker, Laboratoire de Génétique Moléculaire, Paris, France.,AP-HP, Centre de référence «Surdités génétiques», Hôpital Necker, Paris, France
| | - Albert David
- Centre hospitalier universitaire de Nantes, Service de Génétique Médicale, Nantes, France
| | - Yves Sznajer
- Centre de génétique humaine, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium
| | - Patricia Blanchet
- Centre Hospitalier Universitaire de Montpellier, Département de Génétique Médicale, Montpellier, France
| | - Sandrine Marlin
- INSERM U1163, Institut IMAGINE, Equipe Embryologie et Génétique des Malformations Humaines, Paris, France.,AP-HP, Centre de référence «Surdités génétiques», Hôpital Necker, Paris, France
| | - Veronique Pingault
- INSERM U955, IMRB, Equipe 6, Créteil, France.,INSERM U1163, Institut IMAGINE, Equipe Embryologie et Génétique des Malformations Humaines, Paris, France.,AP-HP, Groupe Henri Mondor-Albert Chenevier, Département de Génétique, Créteil, France.,AP-HP, Hôpital Necker, Laboratoire de Génétique Moléculaire, Paris, France.,Université Paris-Descartes, Faculté de Médecine, Paris, France
| |
Collapse
|
|
36
|
Schille C, Schambony A. Signaling pathways and tissue interactions in neural plate border formation. NEUROGENESIS 2017; 4:e1292783. [PMID: 28352644 DOI: 10.1080/23262133.2017.1292783] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 02/02/2017] [Accepted: 02/02/2017] [Indexed: 02/04/2023]
Abstract
The neural crest is a transient cell population that gives rise to various cell types of multiple tissues and organs in the vertebrate embryo. Neural crest cells arise from the neural plate border, a region localized at the lateral borders of the prospective neural plate. Temporally and spatially coordinated interaction with the adjacent tissues, the non-neural ectoderm, the neural plate and the prospective dorsolateral mesoderm, is required for neural plate border specification. Signaling molecules, namely BMP, Wnt and FGF ligands and corresponding antagonists are derived from these tissues and interact to induce the expression of neural plate border specific genes. The present mini-review focuses on the current understanding of how the NPB territory is formed and accentuates the need for coordinated interaction of BMP and Wnt signaling pathways and precise tissue communication that are required for the definition of the prospective NC in the competent ectoderm.
Collapse
Affiliation(s)
- Carolin Schille
- Biology Department, Developmental Biology, Friedrich-Alexander University Erlangen-Nuremberg , Erlangen, Germany
| | - Alexandra Schambony
- Biology Department, Developmental Biology, Friedrich-Alexander University Erlangen-Nuremberg , Erlangen, Germany
| |
Collapse
|
|
37
|
Abstract
Background: Much progress has been made in recent years in the identification of genes underlying many hereditary skin diseases. Objective: To provide an update on the status of the identification of genes involved in hereditary skin disorders and to compare the current standing with that in the last decade. Methods: A review of the literature is presented here in a series of lists describing the chromosomal location, specific gene, clinical relevance, and availability of molecular-based genetic tests for each genodermatosis. Results: Progress has been made in identifying the genes underlying many disorders of cornification, genodermatoses with malignant potential, bullous disorders, pigmentary disorders, disorders affecting the epidermal appendages and the dermis, and other miscellaneous genodermatoses. Conclusion: The great progress made toward the completion of the human gene sequence and the continued efforts of many clinical and molecular scientists to identify disease genes will make diagnosis of hereditary dermatological disorders more precise and allow accurate family counseling as well as possibly leading to more targeted therapies during this millennium.
Collapse
|
|
38
|
Signaling Pathways in Melanogenesis. Int J Mol Sci 2016; 17:ijms17071144. [PMID: 27428965 PMCID: PMC4964517 DOI: 10.3390/ijms17071144] [Citation(s) in RCA: 598] [Impact Index Per Article: 66.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 06/03/2016] [Accepted: 07/08/2016] [Indexed: 12/25/2022] Open
Abstract
Melanocytes are melanin-producing cells found in skin, hair follicles, eyes, inner ear, bones, heart and brain of humans. They arise from pluripotent neural crest cells and differentiate in response to a complex network of interacting regulatory pathways. Melanins are pigment molecules that are endogenously synthesized by melanocytes. The light absorption of melanin in skin and hair leads to photoreceptor shielding, thermoregulation, photoprotection, camouflage and display coloring. Melanins are also powerful cation chelators and may act as free radical sinks. Melanin formation is a product of complex biochemical events that starts from amino acid tyrosine and its metabolite, dopa. The types and amounts of melanin produced by melanocytes are determined genetically and are influenced by a variety of extrinsic and intrinsic factors such as hormonal changes, inflammation, age and exposure to UV light. These stimuli affect the different pathways in melanogenesis. In this review we will discuss the regulatory mechanisms involved in melanogenesis and explain how intrinsic and extrinsic factors regulate melanin production. We will also explain the regulatory roles of different proteins involved in melanogenesis.
Collapse
|
|
39
|
The Hearing Outcomes of Cochlear Implantation in Waardenburg Syndrome. BIOMED RESEARCH INTERNATIONAL 2016; 2016:2854736. [PMID: 27376080 PMCID: PMC4916269 DOI: 10.1155/2016/2854736] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 03/27/2016] [Accepted: 05/18/2016] [Indexed: 01/22/2023]
Abstract
Objectives. This study aimed to determine the feasibility of cochlear implantation for sensorineural hearing loss in patients with Waardenburg syndrome. Method. A retrospective chart review was performed on patients who underwent cochlear implantation at the University of Tokyo Hospital. Clinical classification, genetic mutation, clinical course, preoperative hearing threshold, high-resolution computed tomography of the temporal bone, and postoperative hearing outcome were assessed. Result. Five children with Waardenburg syndrome underwent cochlear implantation. The average age at implantation was 2 years 11 months (ranging from 1 year 9 months to 6 years 3 months). Four patients had congenital profound hearing loss and one patient had progressive hearing loss. Two patients had an inner ear malformation of cochlear incomplete partition type 2. No surgical complication or difficulty was seen in any patient. All patients showed good hearing outcome postoperatively. Conclusion. Cochlear implantation could be a good treatment option for Waardenburg syndrome.
Collapse
|
|
40
|
Saldana-Caboverde A, Perera EM, Watkins-Chow DE, Hansen NF, Vemulapalli M, Mullikin JC, Pavan WJ, Kos L. The transcription factors Ets1 and Sox10 interact during murine melanocyte development. Dev Biol 2015; 407:300-12. [PMID: 25912689 PMCID: PMC4618791 DOI: 10.1016/j.ydbio.2015.04.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Revised: 04/06/2015] [Accepted: 04/07/2015] [Indexed: 11/19/2022]
Abstract
Melanocytes, the pigment-producing cells, arise from multipotent neural crest (NC) cells during embryogenesis. Many genes required for melanocyte development were identified using mouse pigmentation mutants. The variable spotting mouse pigmentation mutant arose spontaneously at the Jackson Laboratory. We identified a G-to-A nucleotide transition in exon 3 of the Ets1 gene in variable spotting, which results in a missense G102E mutation. Homozygous variable spotting mice exhibit sporadic white spotting. Similarly, mice carrying a targeted deletion of Ets1 exhibit hypopigmentation; nevertheless, the function of Ets1 in melanocyte development is unknown. The transcription factor Ets1 is widely expressed in developing organs and tissues, including the NC. In the chick, Ets1 is required for the expression of Sox10, a transcription factor critical for the development of various NC derivatives, including melanocytes. We show that Ets1 is required early for murine NC cell and melanocyte precursor survival in vivo. Given the importance of Ets1 for Sox10 expression in the chick, we investigated a potential genetic interaction between these genes by comparing the hypopigmentation phenotypes of single and double heterozygous mice. The incidence of hypopigmentation in double heterozygotes was significantly greater than in single heterozygotes. The area of hypopigmentation in double heterozygotes was significantly larger than would be expected from the addition of the areas of hypopigmentation of single heterozygotes, suggesting that Ets1 and Sox10 interact synergistically in melanocyte development. Since Sox10 is also essential for enteric ganglia development, we examined the distal colons of Ets1 null mutants and found a significant decrease in enteric innervation, which was exacerbated by Sox10 heterozygosity. At the molecular level, Ets1 was found to activate an enhancer critical for Sox10 expression in NC-derived structures. Furthermore, enhancer activation was significantly inhibited by the variable spotting mutation. Together, these results suggest that Ets1 and Sox10 interact to promote proper melanocyte and enteric ganglia development from the NC.
Collapse
Affiliation(s)
| | - Erasmo M Perera
- Department of Biological Sciences, Florida International University, Miami, FL, USA
| | - Dawn E Watkins-Chow
- Genetic Disease Research Branch, National Human Genome Institute, National Institutes of Health, Bethesda, MD, USA
| | - Nancy F Hansen
- Comparative Genomics Analysis Unit, CGCGB, National Human Genome Research Institute, Bethesda, MD, USA
| | - Meghana Vemulapalli
- NIH Intramural Sequencing Center, National Human Genome Research Institute, Rockville, MD, USA
| | - James C Mullikin
- Comparative Genomics Analysis Unit, CGCGB, National Human Genome Research Institute, Bethesda, MD, USA; NIH Intramural Sequencing Center, National Human Genome Research Institute, Rockville, MD, USA
| | - William J Pavan
- Genetic Disease Research Branch, National Human Genome Institute, National Institutes of Health, Bethesda, MD, USA
| | - Lidia Kos
- Department of Biological Sciences, Florida International University, Miami, FL, USA; Biomolecular Sciences Institute, Florida International University, Miami, FL.
| |
Collapse
|
|
41
|
Abstract
The development of the vertebrate skeleton reflects its evolutionary history. Cartilage formation came before biomineralization and a head skeleton evolved before the formation of axial and appendicular skeletal structures. This review describes the processes that result in endochondral and intramembranous ossification, the important roles of growth and transcription factors, and the consequences of mutations in some of the genes involved. Following a summary of the origin of cartilage, muscle, and tendon cell lineages in the axial skeleton, we discuss the role of muscle forces in the formation of skeletal architecture and assembly of musculoskeletal functional units. Finally, ontogenetic patterning of bones in response to mechanical loading is reviewed.This article is part of a Special Issue entitled "Muscle Bone Interactions".
Collapse
Affiliation(s)
- Agnes D Berendsen
- Department of Developmental Biology, Harvard School of Dental Medicine, Harvard University, USA
| | - Bjorn R Olsen
- Department of Developmental Biology, Harvard School of Dental Medicine, Harvard University, USA.
| |
Collapse
|
|
42
|
Abstract
Hearing loss (HL) is one of the most common birth defects in developed countries and is a diverse pathologic condition with different classifications. One of these is based on the association with other clinical features, defined as syndromic hearing loss (SHL). Determining the cause of the HL in these patients is extremely beneficial as it enables a personalized approach to caring for the individual. Early screening can further aid in optimal rehabilitation for a child's development and growth. The advancement of high-throughput sequencing technology is facilitating rapid and low-cost diagnostics for patients with SHL.
Collapse
Affiliation(s)
- Tal Koffler
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Kathy Ushakov
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Karen B Avraham
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel.
| |
Collapse
|
|
43
|
Monsoro-Burq AH. PAX transcription factors in neural crest development. Semin Cell Dev Biol 2015; 44:87-96. [PMID: 26410165 DOI: 10.1016/j.semcdb.2015.09.015] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 09/14/2015] [Accepted: 09/21/2015] [Indexed: 10/23/2022]
Abstract
The nine vertebrate PAX transcription factors (PAX1-PAX9) play essential roles during early development and organogenesis. Pax genes were identified in vertebrates using their homology with the Drosophila melanogaster paired gene DNA-binding domain. PAX1-9 functions are largely conserved throughout vertebrate evolution, in particular during central nervous system and neural crest development. The neural crest is a vertebrate invention, which gives rise to numerous derivatives during organogenesis, including neurons and glia of the peripheral nervous system, craniofacial skeleton and mesenchyme, the heart outflow tract, endocrine and pigment cells. Human and mouse spontaneous mutations as well as experimental analyses have evidenced the critical and diverse functions of PAX factors during neural crest development. Recent studies have highlighted the role of PAX3 and PAX7 in neural crest induction. Additionally, several PAX proteins - PAX1, 3, 7, 9 - regulate cell proliferation, migration and determination in multiple neural crest-derived lineages, such as cardiac, sensory, and enteric neural crest, pigment cells, glia, craniofacial skeleton and teeth, or in organs developing in close relationship with the neural crest such as the thymus and parathyroids. The diverse PAX molecular functions during neural crest formation rely on fine-tuned modulations of their transcriptional transactivation properties. These modulations are generated by multiple means, such as different roles for the various isoforms (formed by alternative splicing), or posttranslational modifications which alter protein-DNA binding, or carefully orchestrated protein-protein interactions with various co-factors which control PAX proteins activity. Understanding these regulations is the key to decipher the versatile roles of PAX transcription factors in neural crest development, differentiation and disease.
Collapse
Affiliation(s)
- Anne H Monsoro-Burq
- Univ. Paris Sud, Université Paris Saclay, Centre Universitaire, 15, rue Georges Clémenceau, F-91405 Orsay, France; Institut Curie Research Division, Centre Universitaire, 15, rue Georges Clémenceau, F-91405 Orsay, France; UMR 3347 CNRS, U1021 Inserm, Université Paris Saclay, Centre Universitaire, 15, rue Georges Clémenceau, F-91405 Orsay, France.
| |
Collapse
|
|
44
|
Cao J, Dai X, Wan L, Wang H, Zhang J, Goff PS, Sviderskaya EV, Xuan Z, Xu Z, Xu X, Hinds P, Flaherty KT, Faller DV, Goding CR, Wang Y, Wei W, Cui R. The E3 ligase APC/C(Cdh1) promotes ubiquitylation-mediated proteolysis of PAX3 to suppress melanocyte proliferation and melanoma growth. Sci Signal 2015; 8:ra87. [PMID: 26329581 DOI: 10.1126/scisignal.aab1995] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The anaphase-promoting complex or cyclosome with the subunit Cdh1 (APC/C(Cdh1)) is an E3 ubiquitin ligase involved in the control of the cell cycle. Here, we identified sporadic mutations occurring in the genes encoding APC components, including Cdh1, in human melanoma samples and found that loss of APC/C(Cdh1) may promote melanoma development and progression, but not by affecting cell cycle regulatory targets of APC/C. Most of the mutations we found in CDH1 were those associated with ultraviolet light (UV)-induced melanomagenesis. Compared with normal human skin tissue and human or mouse melanocytes, the abundance of Cdh1 was decreased and that of the transcription factor PAX3 was increased in human melanoma tissue and human or mouse melanoma cell lines, respectively; Cdh1 abundance was further decreased with advanced stages of human melanoma. PAX3 was a substrate of APC/C(Cdh1) in melanocytes, and APC/C(Cdh1)-mediated ubiquitylation marked PAX3 for proteolytic degradation in a manner dependent on the D-box motif in PAX3. Either mutating the D-box in PAX3 or knocking down Cdh1 prevented the ubiquitylation and degradation of PAX3 and increased proliferation and melanin production in melanocytes. Knocking down Cdh1 in melanoma cells in culture or before implantation in mice promoted doxorubicin resistance, whereas reexpressing wild-type Cdh1, but not E3 ligase-deficient Cdh1 or a mutant that could not interact with PAX3, restored doxorubicin sensitivity in melanoma cells both in culture and in xenografts. Thus, our findings suggest a tumor suppressor role for APC/C(Cdh1) in melanocytes and that targeting PAX3 may be a strategy for treating melanoma.
Collapse
Affiliation(s)
- Juxiang Cao
- Department of Pharmacology and Experimental Therapeutics, Boston University Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA
| | - Xiangpeng Dai
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
| | - Lixin Wan
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
| | - Hongshen Wang
- Department of Pharmacology and Experimental Therapeutics, Boston University Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA. Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 20032, P. R. China
| | - Jinfang Zhang
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
| | - Philip S Goff
- Molecular Cell Sciences Research Centre, Canadian Cancer Society Research Institute, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK
| | - Elena V Sviderskaya
- Molecular Cell Sciences Research Centre, Canadian Cancer Society Research Institute, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK
| | - Zhenyu Xuan
- Department of Molecular and Cell Biology, The University of Texas at Dallas, Dallas, TX 75080, USA
| | - Zhixiang Xu
- Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35233, USA
| | - Xiaowei Xu
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Philip Hinds
- Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA
| | - Keith T Flaherty
- Cancer Center, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02114, USA
| | - Douglas V Faller
- Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA
| | - Colin R Goding
- Ludwig Institute for Cancer Research, University of Oxford, Headington, Oxford OX3 7DQ, UK
| | - Yongjun Wang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 20032, P. R. China.
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
| | - Rutao Cui
- Department of Pharmacology and Experimental Therapeutics, Boston University Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA. Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 20032, P. R. China.
| |
Collapse
|
|
45
|
Abstract
PURPOSE Hirschsprung's disease (HSCR) is a developmental disorder of the enteric nervous system, which occurs due to the failure of neural crest cell migration. Rodent animal models of aganglionosis have contributed greatly to our understanding of the genetic basis of HSCR. Several natural or target mutations in specific genes have been reported to produce developmental defects in neural crest migration, differentiation or survival. The aim of this study was to review the currently available knockout models of HSCR to better understand the molecular basis of HSCR. METHODS A review of the literature using the keywords "Hirschsprung's disease", "aganglionosis", "megacolon" and "knockout mice model" was performed. Resulting publications were reviewed for relevant mouse models of human aganglionosis. Reference lists were screened for additional relevant studies. RESULTS 16 gene knockout mouse models were identified as relevant rodent models of human HSCR. Due to the deletion of a specific gene, the phenotypes of these knockout models are diverse and range from small bowel dilatation and muscular hypertrophy to total intestinal aganglionosis. CONCLUSIONS Mouse models of aganglionosis have been instrumental in the discovery of the causative genes of HSCR. Although important advances have been made in understanding the genetic basis of HSCR, animal models of aganglionosis in future should further help to identify the unknown susceptibility genes in HSCR.
Collapse
Affiliation(s)
- J Zimmer
- National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
| | | |
Collapse
|
|
46
|
Jalilian N, Tabatabaiefar MA, Farhadi M, Bahrami T, Emamdjomeh H, Noori-Daloii MR. Molecular and clinical characterization of Waardenburg syndrome type I in an Iranian cohort with two novel PAX3 mutations. Gene 2015; 574:302-7. [PMID: 26275939 DOI: 10.1016/j.gene.2015.08.023] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Revised: 08/05/2015] [Accepted: 08/10/2015] [Indexed: 11/15/2022]
Abstract
Waardenburg syndrome (WS) is a disease of abnormal neural-crest derived melanocyte development characterized by hearing loss and pigmentary disturbances in hair, eyes and skin. WS is subdivided into four major types, WS1-WS4, where WS1 is recognized by the presence of dystopia canthorum, with PAX3 being the only known gene involved. This study aimed at investigating PAX3 mutations and clinical characteristics of WS1 in a group of Iranian patients. A total of 12 WS1 patients from four unrelated Iranian families were enrolled. Waardenburg consortium guidelines were used for WS1 diagnosis. A detailed family history was traced and a thorough clinical examination was performed for all participants. Furthermore, WS1 patients underwent screening for PAX3 mutations using PCR-sequencing. Dystopia canthorum, broad high nasal root and synophrys were observed in all patients. Early graying, hair discoloration, hypoplastic blue eyes (characteristic brilliant blue iris) and hearing loss were the most common features observed, while heterochromia iridis was the least frequently observed sign among the studied Iranian WS1 patients. Genetic analysis of PAX3 revealed four mutations including c.667C>T, c.784C>T, c.951delT and c.451+3A>C. Two of the four mutations reported here (c.951delT and c.451+3A>C) are being reported for the first time in this study. Our data provide insight into genotypic and phenotypic spectrum of WS1 in an Iranian series of patients. Our results expand the spectrum of PAX3 mutations and may have implications for the genetic counseling of WS in Iran.
Collapse
Affiliation(s)
- Nazanin Jalilian
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Amin Tabatabaiefar
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran; Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan University Of Medical Sciences, Isfahan, Iran
| | - Mohammad Farhadi
- Department and Research Center of Otolaryngology, Head and Neck Surgery, Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, IR Iran
| | - Tayeb Bahrami
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hesam Emamdjomeh
- Department and Research Center of Otolaryngology, Head and Neck Surgery, Hazrat Rasoul Akram Hospital, Iran University of Medical Sciences, Tehran, IR Iran
| | - Mohammad Reza Noori-Daloii
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
47
|
Mayran A, Pelletier A, Drouin J. Pax factors in transcription and epigenetic remodelling. Semin Cell Dev Biol 2015; 44:135-44. [PMID: 26234816 DOI: 10.1016/j.semcdb.2015.07.007] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Revised: 07/22/2015] [Accepted: 07/24/2015] [Indexed: 11/25/2022]
Abstract
The nine Pax transcription factors that constitute the mammalian family of paired domain (PD) factors play key roles in many developmental processes. As DNA binding transcription factors, they exhibit tremendous variability and complexity in their DNA recognition patterns. This is ascribed to the presence of multiple DNA binding structural domains, namely helix-turn-helix (HTH) domains. The PD contains two HTH subdomains and four of the nine Pax factors have an additional HTH domain, the homeodomain (HD). We now review these diverse DNA binding modalities together with their properties as transcriptional activators and repressors. The action of Pax factors on gene expression is also exerted through recruitment of chromatin remodelling complexes that introduce either activating or repressive chromatin marks. Interestingly, the recent demonstration that Pax7 has pioneer activity, the unique property to "open" chromatin, further underlines the mechanistic versatility and the developmental importance of these factors.
Collapse
Affiliation(s)
- Alexandre Mayran
- Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada
| | - Audrey Pelletier
- Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada
| | - Jacques Drouin
- Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada.
| |
Collapse
|
|
48
|
Song J, Feng Y, Acke FR, Coucke P, Vleminckx K, Dhooge IJ. Hearing loss in Waardenburg syndrome: a systematic review. Clin Genet 2015; 89:416-425. [PMID: 26100139 DOI: 10.1111/cge.12631] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Revised: 06/18/2015] [Accepted: 06/18/2015] [Indexed: 01/14/2023]
Abstract
Waardenburg syndrome (WS) is a rare genetic disorder characterized by hearing loss (HL) and pigment disturbances of hair, skin and iris. Classifications exist based on phenotype and genotype. The auditory phenotype is inconsistently reported among the different Waardenburg types and causal genes, urging the need for an up-to-date literature overview on this particular topic. We performed a systematic review in search for articles describing auditory features in WS patients along with the associated genotype. Prevalences of HL were calculated and correlated with the different types and genes of WS. Seventy-three articles were included, describing 417 individual patients. HL was found in 71.0% and was predominantly bilateral and sensorineural. Prevalence of HL among the different clinical types significantly differed (WS1: 52.3%, WS2: 91.6%, WS3: 57.1%, WS4: 83.5%). Mutations in SOX10 (96.5%), MITF (89.6%) and SNAI2 (100%) are more frequently associated with hearing impairment than other mutations. Of interest, the distinct disease-causing genes are able to better predict the auditory phenotype compared with different clinical types of WS. Consequently, it is important to confirm the clinical diagnosis of WS with molecular analysis in order to optimally inform patients about the risk of HL.
Collapse
Affiliation(s)
- J Song
- Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Y Feng
- Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - F R Acke
- Department of Otorhinolaryngology, Ghent University/Ghent University Hospital, Ghent, Belgium
| | - P Coucke
- Department of Medical Genetics, Ghent University/Ghent University Hospital, Ghent, Belgium
| | - K Vleminckx
- Department of Medical Genetics, Ghent University/Ghent University Hospital, Ghent, Belgium.,Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - I J Dhooge
- Department of Otorhinolaryngology, Ghent University/Ghent University Hospital, Ghent, Belgium
| |
Collapse
|
|
49
|
Nishio SY, Hattori M, Moteki H, Tsukada K, Miyagawa M, Naito T, Yoshimura H, Iwasa YI, Mori K, Shima Y, Sakuma N, Usami SI. Gene expression profiles of the cochlea and vestibular endorgans: localization and function of genes causing deafness. Ann Otol Rhinol Laryngol 2015; 124 Suppl 1:6S-48S. [PMID: 25814645 DOI: 10.1177/0003489415575549] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
OBJECTIVES We sought to elucidate the gene expression profiles of the causative genes as well as the localization of the encoded proteins involved in hereditary hearing loss. METHODS Relevant articles (as of September 2014) were searched in PubMed databases, and the gene symbols of the genes reported to be associated with deafness were located on the Hereditary Hearing Loss Homepage using localization, expression, and distribution as keywords. RESULTS Our review of the literature allowed us to systematize the gene expression profiles for genetic deafness in the inner ear, clarifying the unique functions and specific expression patterns of these genes in the cochlea and vestibular endorgans. CONCLUSIONS The coordinated actions of various encoded molecules are essential for the normal development and maintenance of auditory and vestibular function.
Collapse
Affiliation(s)
- Shin-Ya Nishio
- Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto, Japan
| | - Mitsuru Hattori
- Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hideaki Moteki
- Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Keita Tsukada
- Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Maiko Miyagawa
- Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takehiko Naito
- Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hidekane Yoshimura
- Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yoh-Ichiro Iwasa
- Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Kentaro Mori
- Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yutaka Shima
- Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Naoko Sakuma
- Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan Department of Otorhinolaryngology and Head and Neck Surgery, Yokohama City University School of Medicine, Yokohama, Japan
| | - Shin-Ichi Usami
- Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan Department of Hearing Implant Sciences, Shinshu University School of Medicine, Matsumoto, Japan
| |
Collapse
|
|
50
|
Kontorinis G, Goetz F, Lanfermann H, Luytenski S, Giesemann AM. Inner ear anatomy in Waardenburg syndrome: radiological assessment and comparison with normative data. Int J Pediatr Otorhinolaryngol 2014; 78:1320-6. [PMID: 24882458 DOI: 10.1016/j.ijporl.2014.05.020] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2013] [Revised: 05/12/2014] [Accepted: 05/14/2014] [Indexed: 11/24/2022]
Abstract
OBJECTIVE As patients with Waardenburg syndrome (WS) represent potential candidates for cochlear implantation, their inner ear anatomy is of high significance. There is an ongoing debate whether WS is related to any inner ear dysplasias. Our objective was to evaluate radiologically the inner ear anatomy in patients with WS and identify any temporal bone malformations. METHODS A retrospective case review was carried out in a tertiary, referral center. The high resolution computed tomography (HRCT) scans of the temporal bone from 20 patients (40 ears) with WS who were managed for deafness in a tertiary referral center from 1995 to 2012 were retrospectively examined. Measurements of 15 different inner ear dimensions, involving the cochlea, the vestibule, the semicircular canals and the internal auditory meatus, as well as measurements of the vestibular aqueduct, were performed independently by two neuroradiologists. Finally, we compared the results from the WS group with a control group consisting of 50 normal hearing subjects (100 ears) and with previously reported normative values. RESULTS Inner ear malformations were not found in any of the patients with WS. All measured inner ear dimensions were within the normative values compiled by our study group as well as by others. CONCLUSIONS Inner ear malformations are not characteristic for all types of WS; however, certain rare subtypes might be related to inner ear deformities. Normative cochleovestibular dimensions that can help in assessing the temporal bone anatomy are provided.
Collapse
Affiliation(s)
- Georgios Kontorinis
- Department of Otolaryngology, Hannover Medical School, 1 Carl-Neuberg-Str., Hannover 30625, Germany; Department of Otolaryngology, Glasgow Southern Teaching Hospital, 1345 Govan Road, Glasgow G51 4TF, United Kingdom.
| | - Friedrich Goetz
- Department of Neuroradiology, Hannover Medical School, 1 Carl-Neuberg-Str., Hannover 30625, Germany
| | - Heinrich Lanfermann
- Department of Neuroradiology, Hannover Medical School, 1 Carl-Neuberg-Str., Hannover 30625, Germany
| | - Stefan Luytenski
- Department of Otolaryngology, Hannover Medical School, 1 Carl-Neuberg-Str., Hannover 30625, Germany
| | - Anja M Giesemann
- Department of Neuroradiology, Hannover Medical School, 1 Carl-Neuberg-Str., Hannover 30625, Germany
| |
Collapse
|