ESPE Abstracts (2016) 86 FC12.4

Idiopathic Hypogonadotrophic Hypogonadism Caused by Inactivating Mutations in SRA1

Leman Damla Kotana, Charlton Cooperb, Sukran Darcanc, Ian Carrd, Samim Ozenc, Yi Yanb, Mohammad K. Hamedanib, Fatih Gurbuza, Eda Mengena, Ihsan Turana, Ayca Ulubaye, Gamze Akkusf, Bilgin Yuksela, Etienne Leygueb & Kemal Topaloglua

aCukurova University, Division of Pediatric Endocrinology,
Adana, Turkey; bUniversity of Manitoba, Manitoba, Canada;
cEge University, Izmir, Turkey; dUniversity of Leeds, Leeds, UK; eDepartment of Forensic Medicine, Cukurova University, Adana, Turkey; fCukurova University, Division of Endocrinology, Adana, Turkey

Background: What initiates pubertal process in humans and other mammals has remained elusive.

Objective and hypotheses: We hypothesize that gene(s), whose products trigger the GnRH pulse generator to restart ticking at the usual time of puberty, can be identified via autozygosity mapping together with whole exome sequencing in patients with idiopathic hypogonadotrophic hypogonadism (IHH).

Method: We studied a cohort IHH cases. Functional implications of variants were tested by a luciferase reporter assay in HeLa cells.

Results: Our studies revealed three independent families in which IHH is associated with inactivating SRA1 variants. Functional studies with a mutant SRA1 construct showed a reduced co-activation of ligand dependent activity of the estrogen receptor alpha.

Conclusion: SRA1 acts as a protein as well as a noncoding functional RNA product. These products function as co-regulators of nuclear receptors including sex steroid receptors as well as SF-1 and LRH-1, the master regulators of steroidogenesis. 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 versatility, and complexity of puberty.