# Genetic variants in HELB contribute to premature ovarian insufficiency and early age of natural menopause

## TL;DR

This study shows that genetic variants in HELB are linked to early ovarian failure and menopause, based on findings in humans and mice.

## Contribution

The study identifies HELB as a novel gene involved in female reproductive aging and ovarian function.

## Key findings

- A rare HELB variant was found in a family with premature ovarian insufficiency and early menopause.
- Helb-mutated mice showed reduced fertility and accelerated ovarian aging.
- Transcriptomic analysis revealed disrupted gene expression related to ovarian function in Helb-mutated mice.

## Abstract

Premature ovarian insufficiency (POI) is a complex reproductive disorder with a strong genetic component. The known POI causative genes currently account for only a small fraction of cases. In this study, we conducted whole-exome sequencing and identified a rare heterozygous missense variant in DNA helicase B (HELB) (c.349G>T, p.Asp117Tyr) in a Chinese family with POI and early menopause. To investigate the pathogenicity of this variant, a knockin mouse model carrying a heterozygous missense Helb variant (Helb+/D112Y) homologous to the human HELB c.349G>T was constructed. The Helb-mutated female mice exhibited reduced litter sizes and prolonged interlitter intervals compared with wild-type mice after reaching 10 months of age, leading to a shortened reproductive lifespan. Consistently, aged Helb+/D112Y females showed decreased ovarian weight and accelerated follicle depletion. Transcriptomic analysis of the ovaries from Helb-mutated mice revealed dysregulated expression of genes associated with impaired ovarian function and ovarian aging. Collectively, these findings in both humans and mice suggest that HELB is involved in maintaining ovarian function and regulating reproductive aging, highlighting the importance of HELB in female reproductive health.

HELB is involved in regulating female reproductive aging and genetic variants in HELB contribute to premature ovarian insufficiency and early age of natural menopause.