| Full text | |
| Author(s): Show less - |
Correa-Silva, Silvia Regina
[1]
;
Fausto, Jessica da Silva
[1]
;
Letro Kizys, Marina Malta
[1]
;
Filipelli, Rafael
[2]
;
Marco Antonio, David Santos
[3]
;
Oku, Andre Yuji
[3]
;
Furuzawa, Gilberto Koiti
[1]
;
Hernandez Orchard, Eugenia Veronica
[4]
;
Costa-Barbosa, Flavia Amanda
[3, 1]
;
Mitne-Neto, Miguel
[3, 5]
;
Dias-da-Silva, Magnus R.
[1]
Total Authors: 11
|
| Affiliation: | [1] Univ Fed Sao Paulo, Lab Mol & Translat Endocrinol, Dept Med, Escola Paulista Med, Sao Paulo - Brazil
[2] Univ Fed Sao Paulo, Mol Biol & Lysosomal Dis Diag Lab, Dept Biophys, Escola Paulista Med, Sao Paulo - Brazil
[3] Fleury Grp, Res & Dev, Sao Paulo - Brazil
[4] Unimed Belo Horizonte, Belo Horizonte, MG - Brazil
[5] Univ Sao Paulo, Human Genome & Stem Cell Res Ctr HUG CELL, Biosci Inst, Sao Paulo - Brazil
Total Affiliations: 5
|
| Document type: | Journal article |
| Source: | Journal of Neuroendocrinology; v. 30, n. 12 DEC 2018. |
| Web of Science Citations: | 1 |
| Abstract | |
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. (AU) | |
| FAPESP's process: | 06/60402-1 - Medular carcinoma of the thyroid: revisiting the clinical, molecular biological, biochemical and biological aspects following findings of molecular genetics |
| Grantee: | Rui Monteiro de Barros Maciel |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 12/00079-3 - Thyroid dysgenesis: screening and functional analyses of mutations of the candidate-genes NKX2.5, HAND2, ISL1, TBX1, HOXA3/HOXB3/HOXD3 and EYA1 in a cohort of 601 patients with congenital hypothyroidism |
| Grantee: | Rui Monteiro de Barros Maciel |
| Support Opportunities: | Regular Research Grants |