Homozygous Variant in KASH5 Causes Premature Ovarian Insufficiency by Disordered Meiotic Homologous Pairing.

CONTEXT: Premature ovarian insufficiency (POI) affects 1% to 3.7% of women at reproductive age, and its etiology is heterogeneous. The linker of nucleoskeleton and cytoskeleton (LINC) complex, consisting of KASH5 and SUN1, plays an indispensable role in meiotic homolog pairing, determining the ovarian reserve. However, their roles in the pathogenesis of POI are unknown. OBJECTIVE: To investigate the role of KASH5 variation in the pathogenesis of POI. DESIGN: Whole-exome sequencing was performed in a pedigree with 2 POI patients. The pathogenicity of identified variant was illustrated by in vitro functional studies, and its effect on ovarian function and meiosis was confirmed by histological analysis and oocyte spreads with Kash5 C-terminal deleted mice model. RESULTS: A homozygous splicing site variant in KASH5 (c.747G > A) was identified. In vitro studies found the variant disturbed the nuclear membrane localization of KASH5 and its binding with SUN1. Moreover, the Kash5 C-terminal deleted mice revealed defective meiotic homolog pairing and accelerated depletion of oocytes. CONCLUSIONS: The splicing site variant in KASH5 is responsible for POI due to defective meiotic homolog pairing and accelerated depletion of oocytes. Our study is the first to report disorganized LINC complex participating in POI pathogenesis, potentially suggesting the essential roles of meiotic telomere attachment and dynein-driven proteins for chromosome movement in ovarian function maintenance.

Pathogenic Variations of Homologous Recombination Gene HSF2BP Identified in Sporadic Patients With Premature Ovarian Insufficiency.

Premature ovarian insufficiency (POI) is defined as depletion of ovarian function before 40 years of age, which affects 3.7% of women in reproductive age. The etiology of POI is heterogeneous. Recently, with the widespread use of whole-exome sequencing (WES), the DNA repair genes, especially for those involved in meiosis progress, were enriched in the causative gene spectrum of POI. In this study, through the largest in-house WES database of 1,030 patients with sporadic POI, we identified two novel homozygous variations in HSF2BP (c.382T>C, p.C128R; c.557T>C, p.L186P). An in vitro functional study revealed that both variations impaired the nuclear location of HSF2BP and affected its DNA repair capacity. Our studies highlighted the essential role of meiotic homologous recombination genes in the pathogenesis of sporadic POI.