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Idiopathic Hypogonadotropic Hypogonadism Caused by Inactivating Mutations in SRA1.


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.

SUBMITTER: Kotan LD 

PROVIDER: S-EPMC5096466 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Idiopathic Hypogonadotropic Hypogonadism Caused by Inactivating Mutations in SRA1.

Kotan Leman Damla LD   Cooper Charlton C   Darcan Şükran Ş   Carr Ian M IM   Özen Samim S   Yan Yi Y   Hamedani Mohammad K MK   Gürbüz Fatih F   Mengen Eda E   Turan İhsan İ   Ulubay Ayça A   Akkuş Gamze G   Yüksel Bilgin B   Topaloğlu A Kemal AK   Leygue Etienne E  

Journal of clinical research in pediatric endocrinology 20160418 2


<h4>Objective</h4>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).<h4>Methods</h4>A cohort of IHH cases was studied based on autozygosity mapping coupled with whole exome sequencing.<h4>Results</h4>Our studies revealed three independent families in which IHH/delayed puberty is associated with inactivating  ...[more]

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