POU6F2mutation identified in humans with pubertal failure shifts isoform formation and alters GnRH transcript expression

Abstract

Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by absent pubertal development and infertility, often due to gonadotropin-releasing hormone (GnRH) deficits. Exome sequencing of two independent cohorts of IHH patients identified 12 rare missense variants inPOU6F2. POU6F2encodes two distinct isoforms. In mouse, pituitary and gonads expressed both isoforms, but only isoform1 was detected in GnRH cells. Although the function of isoform2 is well known, using bioinformatics and cells assays on a human-derived GnRH cell line, we demonstrate isoform1 can also act as a transcriptional regulator, decreasingGNRH1expression. The impact of twoPOU6F2variants (MT1 and MT2) was then examined. MT1, but not MT2, reduced transcriptional activity of either isoform, preventing Hes5 promoter activation by isoform2 and repression of GnRH transcripts by isoform1. GnRH transcription increases as the cells migrate into the brain. Augmentation earlier can disrupt normal GnRH cell migration, consistent with POU6F2 variants contributing to IHH pathogenesis.

Risk of Sperm Disorders and Impaired Fertility in Frozen–Thawed Bull Semen: A Genome-Wide Association Study

“…POU6F2 belongs to the POU domain family of transcription factors and is known to regulate gene expression in various tissues and at various developmental stages [43]. Previous studies demonstrated that POU6F2 is expressed in the testes and epididymis of mice and humans [44,45], assuming its involvement in spermatogenesis and sperm maturation. Moreover, knockout of this gene led to increased expression of prolactin [46].…”