دورية أكاديمية
A novel GNRHR gene mutation causing congenital hypogonadotrophic hypogonadism in a Brazilian kindred.
| العنوان: | A novel GNRHR gene mutation causing congenital hypogonadotrophic hypogonadism in a Brazilian kindred. |
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| المؤلفون: | Correa-Silva SR; Laboratory of Molecular and Translational Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil., Fausto JDS; Laboratory of Molecular and Translational Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil., Kizys MML; Laboratory of Molecular and Translational Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil., Filipelli R; Molecular Biology and Lysosomal Disease Diagnosis Laboratory, Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil., Marco Antonio DS; Research and Development, Fleury Group, São Paulo, Brazil., Oku AY; Research and Development, Fleury Group, São Paulo, Brazil., Furuzawa GK; Laboratory of Molecular and Translational Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil., Orchard EVH; Unimed Belo Horizonte, Belo Horizonte, Brazil., Costa-Barbosa FA; Laboratory of Molecular and Translational Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.; Research and Development, Fleury Group, São Paulo, Brazil., Mitne-Neto M; Research and Development, Fleury Group, São Paulo, Brazil.; Human Genome and Stem Cell Research Center (HUG-CELL), Biosciences Institute, University of São Paulo (USP), São Paulo, Brazil., Dias-da-Silva MR; Laboratory of Molecular and Translational Endocrinology, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil. |
| المصدر: | Journal of neuroendocrinology [J Neuroendocrinol] 2018 Dec; Vol. 30 (12), pp. e12658. Date of Electronic Publication: 2018 Dec 19. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Wiley & Sons Country of Publication: United States NLM ID: 8913461 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1365-2826 (Electronic) Linking ISSN: 09538194 NLM ISO Abbreviation: J Neuroendocrinol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: <2010->: Malden, MA : Wiley & Sons Original Publication: Eynsham, Oxon, UK : Oxford University Press, c1989- |
| مواضيع طبية MeSH: | Pedigree*, Genetic Predisposition to Disease/*genetics , Hypogonadism/*genetics , Receptors, LHRH/*genetics, Brazil ; Cells, Cultured ; Female ; Humans ; Inositol Phosphates/metabolism ; Male ; Mutation ; Receptors, LHRH/physiology ; Exome Sequencing |
| مستخلص: | Congenital hypogonadotrophic hypogonadism (CHH) is a challenging inherited endocrine disorder characterised by absent or incomplete pubertal development and infertility as a result of the low action/secretion of the hypothalamic gonadotrophin-releasing hormone (GnRH). Given a growing list of gene mutations accounting for CHH, the application of massively parallel sequencing comprises an excellent molecular diagnostic approach because it enables the simultaneous evaluation of many genes. The present study proposes the use of whole exome sequencing (WES) to identify causative and modifying mutations based on a phenotype-genotype CHH analysis using an in-house exome pipeline. Based on 44 known genes related to CHH in humans, we were able to identify a novel homozygous gonadotrophin-releasing hormone receptor (GNRHR) p.Thr269Met mutant, which segregates with the CHH kindred and was predicted to be deleterious by in silico analysis. A functional study measuring intracellular inositol phosphate (IP) when stimulated with GnRH on COS-7 cells confirmed that the p.Thr269Met GnRHR mutant performed greatly diminished IP accumulation relative to the transfected wild-type GnRHR. Additionally, the proband carries three heterozygous variants in CCDC141 and one homozygous in SEMA3A gene, although their effects with respect to modifying the phenotype are uncertain. Because they do not segregate with reproductive phenotype in family members, we advocate they do not contribute to CHH oligogenicity. WES proved to be useful for CHH molecular diagnosis and reinforced its benefit with respect to identifying heterogeneous genetic disorders. Our findings expand the GnRHR mutation spectrum and phenotype-genotype correlation in CHH. (© 2018 British Society for Neuroendocrinology.) |
| فهرسة مساهمة: | Keywords: GNRHR; congenital hypogonadotrophic hypogonadism; exome sequencing |
| المشرفين على المادة: | 0 (GNRHR protein, human) 0 (Inositol Phosphates) 0 (Receptors, LHRH) |
| تواريخ الأحداث: | Date Created: 20181112 Date Completed: 20190930 Latest Revision: 20221207 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1111/jne.12658 |
| PMID: | 30415482 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1365-2826 |
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| DOI: | 10.1111/jne.12658 |