Idiopathic Hypogonadotropic Hypogonadism Caused by Inactivating Mutations in SRA1

Abstract

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.

GnRH Deficient Patients With Congenital Hypogonadotropic Hypogonadism: Novel Genetic Findings in ANOS1, RNF216, WDR11, FGFR1, CHD7, and POLR3A Genes in a Case Series and Review of the Literature

“…The 19-year-old male also carried this same SRA1 variant in heterozygosity together with the novel p.Asp792Asn variant in the RNF216 gene. As reported by Kotan et al ( 25 ), the variant p.Ile179Thr was reported only once in one independent Turkish family with IHH/delayed puberty and its severity was supported by functional studies. Using a mutant SRA1 construct, reduced co-activation of ligand-dependent activity of the estrogen receptor alpha was demonstrated ( 25 ).…”

“…Interestingly, two out of the seven CHH patients in our cohort, a 30-year-old female (Patient 7) and a 19-year-old (Patient 3) male were both identified with variants in the SRA1 gene. More specifically, the 30-year-old female carried in homozygosity the previously reported p.Ile179Thr variant in the SRA1 gene ( 25 ). The 19-year-old male also carried this same SRA1 variant in heterozygosity together with the novel p.Asp792Asn variant in the RNF216 gene.…”

“…The SRA1 is a steroid receptor RNA activator that has been shown to positively regulate the activity of the androgen receptor and the estrogen receptor ( 72 , 73 ). In recent years only a few studies linked the SRA1 gene as responsible for causing CHH when patients inherit pathogenic variants in the AR form ( 25 , 26 ).…”

Expression quantitative trait loci-derived scores and white matter microstructure in UK Biobank: a novel approach to integrating genetics and neuroimaging

“…SRA1 encodes both non-coding and protein-coding RNAs, is implicated in the regulation of numerous nuclear receptor activities, such as metabolism and chromatin organisation, and is known to be expressed in the brain. Kotan et al 38 posited that SRA1 plays a role in the initiation of puberty in humans by finding that inactivating SRA1 variants were associated with idiopathic hypogonadotropic hypogonadism (IHH) in three independent families. IHH is a rare genetic disorder caused by the inability of the hypothalamus to secrete gonadotropin-releasing hormones (GnRH) or by the inability of GnRH to act on pituitary gonadotropes 39 .…”

Targeted Gene Panel Sequencing for Molecular Diagnosis of Kallmann Syndrome and Normosmic Idiopathic Hypogonadotropic Hypogonadism

“…Genomic DNA was extracted from peripheral blood leukocytes using the Gentra Puregene Blood Kit (Qiagen, Hilden, Germany). A targeted panel was designed using 69 genes that were known to be involved in hypothalamus/pituitary development [15][16][17][18][19][20][21][22][23], GnRH neuronal migration [10,11,[24][25][26][27][28][29][30][31][32][33][34], synthesis and secretion of GnRH [35][36][37][38][39][40][41][42], IGD associated neurological disorders [43][44][45][46][47][48], and rare syndromes [26,30,[49][50][51][52][53][54][55][56][57] associated with hypogonadism ( Table 1S, Supporting Information). For compreh...…”