Idiopathic Hypogonadotrophic Hypogonadism Caused by Inactivating Mutations in SRA1

Objective: What initiates pubertal process in humans and other mammals has remained elusive. We hypothesized that gene(s) taking roles in triggering human puberty may be identified by studying a cohort of idiopathic hypogonadotropic hypogonadism (IHH) cases via autozygosity mapping coupled with whole exome sequencing.
Case: Our studies revealed three independent families in which IHH/delayed puberty was 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 versatility and complexity of puberty.