Kotan, LD, Cooper, C, Darcan, Ş et al. (12 more authors) (2016) Idiopathic Hypogonadotropic Hypogonadism Caused by Inactivating Mutations in SRA1. Journal of Clinical Research in Pediatric Endocrinology, 8 (2). pp. 125-134. ISSN 1308-5727
Abstract
What initiates the pubertal process in humans and other mammals is still unknown. We hypothesized that gene(s) taking roles in triggering human puberty may be identified by studying a cohort of idiopathic hypogonadotropic hypogonadism (IHH). A cohort of IHH cases was studied based on autozygosity mapping coupled with whole exome sequencing. Our studies revealed three independent families in which IHH/delayed puberty is associated with inactivating SRA1 variants. SRA1 was the first gene to be identified to function through its protein as well as noncoding functional ribonucleic acid products. These products act as co-regulators of nuclear receptors including sex steroid receptors as well as SF-1 and LRH-1, the master regulators of steroidogenesis. Functional studies with a mutant SRA1 construct showed a reduced co-activation of ligand-dependent activity of the estrogen receptor alpha, as assessed by luciferase reporter assay in HeLa cells. Our findings strongly suggest that SRA1 gene function is required for initiation of puberty in humans. Furthermore, SRA1 with its alternative products and functionality may provide a potential explanation for the versatility and complexity of the pubertal process.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © Journal of Clinical Research in Pediatric Endocrinology. Published by Galenos Publishing. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. |
Keywords: | Hypogonadotropic hypogonadism, puberty, SRA1, PNPLA6, mutation |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Inst of Biomed & Clin Sciences (LIBACS) (Leeds) > Genetics (LIBACS) (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 03 Jan 2018 15:05 |
Last Modified: | 29 Mar 2018 14:38 |
Status: | Published |
Publisher: | Galenos Publishing |
Identification Number: | 10.4274/jcrpe.3248 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:125715 |