HS6ST1 Insufficiency Causes Self-Limited Delayed Puberty in Contrast With Other GnRH Deficiency Genes

Abstract

ContextSelf-limited delayed puberty (DP) segregates in an autosomal-dominant pattern, but the genetic basis is largely unknown. Although DP is sometimes seen in relatives of patients with hypogonadotropic hypogonadism (HH), mutations in genes known to cause HH that segregate with the trait of familial self-limited DP have not yet been identified.ObjectiveTo assess the contribution of mutations in genes known to cause HH to the phenotype of self-limited DP.Design, Patients, and SettingWe performed whole-exome sequencing in 67 probands and 93 relatives from a large cohort of familial self-limited DP, validated the pathogenicity of the identified gene variant in vitro, and examined the tissue expression and functional requirement of the mouse homolog in vivo.ResultsA potentially pathogenic gene variant segregating with DP was identified in 1 of 28 known HH genes examined. This pathogenic variant occurred in HS6ST1 in one pedigree and segregated with the trait in the six affected members with heterozygous transmission (P = 3.01 × 10−5). Biochemical analysis showed that this mutation reduced sulfotransferase activity in vitro. Hs6st1 mRNA was expressed in peripubertal wild-type mouse hypothalamus. GnRH neuron counts were similar in Hs6st1+/− and Hs6st1+/+ mice, but vaginal opening was delayed in Hs6st1+/− mice despite normal postnatal growth.ConclusionsWe have linked a deleterious mutation in HS6ST1 to familial self-limited DP and show that heterozygous Hs6st1 loss causes DP in mice. In this study, the observed overlap in potentially pathogenic mutations contributing to the phenotypes of self-limited DP and HH was limited to this one gene.

EAP1 regulation of GnRH promoter activity is important for human pubertal timing

“…These two variants [NM 024496.3: c.2308A>C (rs760847179) p.Asn770His Chr: 14:77491828 and NM 024496.3: c.661 663delGCG p.Ala221del Chr: 14:77493473] were each identified in one proband from the cohort and their affected family members. The two probands from these pedigrees did not carry any other predicted pathogenic variants in known GnRH deficiency or gonadotropin deficiency-causing genes (16). The two EAP1 variants, p.Asn770His and p.Ala221del, are both rare with a minor allele frequency (MAF) of <0.5% in population databases.…”

“…The cohort of individuals (n = 910) we studied here has been described in previous reports (14)(15)(16). Briefly, the cohort includes patients with self-limited DP (n = 492), defined as the onset of Tanner genital stage II (testicular volume, >3 ml) >13.5 years in boys or Tanner breast stage II >13.0 years in girls (i.e.…”

Genetic regulation in pubertal delay

“…The second gene identified, with a mutation in a large family from the same familial delayed puberty cohort, was the GnRH deficiency gene HS6ST1 (Howard et al 2018b). The pathogenic mutation was found by next-generation sequencing to be carried by six family members from three generations.…”

“…Genetic causes of syndromic and non-syndromic delayed puberty Howard et al 2018b),. TAC3(Zhu et al 2015), TACR3(Zhu et al 2015), IL17RD(Zhu et al 2015), GNRHR(Vaaralahti et al 2011), SEMA3A(Zhu et al 2015) …”

Pesquisa de novos fatores genéticos no atraso constitucional do crescimento e desenvolvimento humano

“…Na última década, foram feitos avanços significativos na elucidação da base genética do ACCD usando-se o sequenciamento paralelo em larga escala (painel gênico e sequenciamento exômico global) (42,43,53) . Variantes raras potencialmente patogênicas foram identificadas em vários genes, incluindo IGSF10 (53) , HS6ST1 (81) , FTO (49) e, mais recentemente EAP1 (55) . GHSR foram os genes afetados mais prevalentes.…”