دورية أكاديمية
Molecular basis of non-syndromic hypospadias: systematic mutation screening and genome-wide copy-number analysis of 62 patients.
| العنوان: | Molecular basis of non-syndromic hypospadias: systematic mutation screening and genome-wide copy-number analysis of 62 patients. |
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| المؤلفون: | Kon M; Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan., Suzuki E; Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan., Dung VC; Department of Endocrinology, The Vietnam National Hospital of Pediatrics, Hanoi, Vietnam., Hasegawa Y; Department of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo 183-8561, Japan., Mitsui T; Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan., Muroya K; Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama 232-0066, Japan., Ueoka K; Division of Urology, National Center for Child Health and Development, Tokyo 157-8535, Japan., Igarashi N; Department of Pediatrics, Toyama Prefectural Central Hospital, Toyama 930-0975, Japan., Nagasaki K; Department of Pediatrics, Niigata University School of Medicine, Niigata 951-8510, Japan., Oto Y; Department of Pediatrics, Dokkyo Medical University Koshigaya Hospital, Koshigaya 343-0845, Japan., Hamajima T; Division of Endocrinology and Metabolism, Aichi Children's Health and Medical Center, Obu 474-8710, Japan., Yoshino K; Department of Urology, Aichi Children's Health and Medical Center, Obu 474-8710, Japan., Igarashi M; Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan., Kato-Fukui Y; Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan., Nakabayashi K; Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan., Hayashi K; Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan., Hata K; Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan., Matsubara Y; National Research Institute for Child Health and Development, Tokyo 157-8535, Japan., Moriya K; Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan., Ogata T; Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan., Nonomura K; Department of Renal and Genitourinary Surgery, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan., Fukami M; Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan fukami-m@ncchd.go.jp. |
| المصدر: | Human reproduction (Oxford, England) [Hum Reprod] 2015 Mar; Vol. 30 (3), pp. 499-506. Date of Electronic Publication: 2015 Jan 20. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press Country of Publication: England NLM ID: 8701199 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2350 (Electronic) Linking ISSN: 02681161 NLM ISO Abbreviation: Hum Reprod Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Oxford, UK : Oxford University Press Original Publication: Oxford ; Washington, DC : Published for the European Society of Human Reproduction and Embryology by IRL Press, [c1986- |
| مواضيع طبية MeSH: | Hypospadias/*genetics, DNA Copy Number Variations ; DNA Mutational Analysis ; Genetic Predisposition to Disease ; Humans ; Male ; Polymorphism, Genetic |
| مستخلص: | Study Question: What percentage of cases with non-syndromic hypospadias can be ascribed to mutations in known causative/candidate/susceptibility genes or submicroscopic copy-number variations (CNVs) in the genome? Summary Answer: Monogenic and digenic mutations in known causative genes and cryptic CNVs account for >10% of cases with non-syndromic hypospadias. While known susceptibility polymorphisms appear to play a minor role in the development of this condition, further studies are required to validate this observation. What Is Known Already: Fifteen causative, three candidate, and 14 susceptible genes, and a few submicroscopic CNVs have been implicated in non-syndromic hypospadias. Study Design, Size, Duration: Systematic mutation screening and genome-wide copy-number analysis of 62 patients. Participants/materials, Setting, Methods: The study group consisted of 57 Japanese and five Vietnamese patients with non-syndromic hypospadias. Systematic mutation screening was performed for 25 known causative/candidate/susceptibility genes using a next-generation sequencer. Functional consequences of nucleotide alterations were assessed by in silico assays. The frequencies of polymorphisms in the patient group were compared with those in the male general population. CNVs were analyzed by array-based comparative genomic hybridization and characterized by fluorescence in situ hybridization. Main Results and the Role of Chance: Seven of 62 patients with anterior or posterior hypospadias carried putative pathogenic mutations, such as hemizygous mutations in AR, a heterozygous mutation in BNC2, and homozygous mutations in SRD5A2 and HSD3B2. Two of the seven patients had mutations in multiple genes. We did not find any rare polymorphisms that were abundant specifically in the patient group. One patient carried mosaic dicentric Y chromosome. Limitations, Reasons for Caution: The patient group consisted solely of Japanese and Vietnamese individuals and clinical and hormonal information of the patients remained rather fragmentary. In addition, mutation analysis focused on protein-altering substitutions. Wider Implications of the Findings: Our data provide evidence that pathogenic mutations can underlie both mild and severe hypospadias and that HSD3B2 mutations cause non-syndromic hypospadias as a sole clinical manifestation. Most importantly, this is the first report documenting possible oligogenicity of non-syndromic hypospadias. Study Funding/competing Interests: This study was funded by the Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology; by the Grant-in-Aid from the Japan Society for the Promotion of Science; by the Grants from the Ministry of Health, Labour and Welfare, from the National Center for Child Health and Development and from the Takeda Foundation. The authors have no competing interests to disclose. Trial Registration Number: Not applicable. (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.) |
| فهرسة مساهمة: | Keywords: copy-number; hypospadias; mutation; polymorphism; susceptibility |
| تواريخ الأحداث: | Date Created: 20150122 Date Completed: 20151109 Latest Revision: 20150214 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1093/humrep/deu364 |
| PMID: | 25605705 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1460-2350 |
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| DOI: | 10.1093/humrep/deu364 |