• PMID: 27086651
• Gene Name: SRA1
• Condition: Idiopathic hypogonadotropic hypogonadism (IHH)
• Association: The 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
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Idiopathic hypogonadotropic hypogonadism (IHH)

Idiopathic Hypogonadotropic Hypogonadism Caused by Inactivating Mutations in SRA1

Kotan LD, Cooper C, Darcan ?, Carr IM, Özen S, Yan Y, Hamedani MK, Gürbüz F, Mengen E, Turan ?, Ulubay A, Akku? G, Yüksel B, Topalo?lu AK, Leygue E.

OBJECTIVE: 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). METHODS: A cohort of IHH cases was studied based on autozygosity mapping coupled with whole exome sequencing. RESULTS: 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. CONCLUSION: 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. FAU - Kotan, Leman Damla AU - Kotan LD FAU - Cooper, Charlton AU - Cooper C FAU - Darcan, Şükran AU - Darcan Ş FAU - Carr, Ian M AU - Carr IM FAU - Özen, Samim AU - Özen S FAU - Yan, Yi AU - Yan Y FAU - Hamedani, Mohammad K AU - Hamedani MK FAU - Gürbüz, Fatih AU - Gürbüz F FAU - Mengen, Eda AU - Mengen E FAU - Turan, İhsan AU - Turan İ FAU - Ulubay, Ayça AU - Ulubay A FAU - Akkuş, Gamze AU - Akkuş G FAU - Yüksel, Bilgin AU - Yüksel B FAU - Topaloğlu, A Kemal AU - Topaloğlu AK AD - Çukurova University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology, Adana, Turkey Phone: +90 322 338 60 60-3148 E-mail: ktopaloglu@cu.edu.tr.