Genetic variants in HELB contribute to premature ovarian insufficiency and early age of natural menopause
Yuncheng Pan, Yuexin Yu, Jitong Mo, Shuting Ren, Zixue Zhou, Xi Yang, Yiqing Liu, Feng Zhang, Yanqin You, Xiaojin Zhang, Yanhua Wu
Yuncheng Pan, Yuexin Yu, Jitong Mo, Shuting Ren, Zixue Zhou, Xi Yang, Yiqing Liu, Feng Zhang, Yanqin You, Xiaojin Zhang, Yanhua Wu
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Research Article Genetics Reproductive biology

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

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.

Authors

Yuncheng Pan, Yuexin Yu, Jitong Mo, Shuting Ren, Zixue Zhou, Xi Yang, Yiqing Liu, Feng Zhang, Yanqin You, Xiaojin Zhang, Yanhua Wu

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Figure 2

Helb+/D112Y knockin mice exhibit reduced female fertility.

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Helb+/D112Y knockin mice exhibit reduced female fertility. (A) Strategy...
(A) Strategy for generating a knockin mouse model carrying a missense mutation in Helb (c.334G>T, p. Asp112Tyr). (B) Sanger sequencing confirmation of wild-type (Helb+/+) and mutant (Helb+/D112Y) mouse genotypes. The mutated position is highlighted in yellow. (C) Cumulative number of pups produced by Helb+/+ and Helb+/D112Y female mice bred continuously with wild-type males for 10 months. n = 5. (D) Average number of pups per litter for female mice. Mice were categorized into 3 age groups: young (2 to 6 months old), middle-aged (7 to 9 months old), and aged (10 to 12 months old). Data are presented as mean ± SD. n = 5. Two-tailed Student’s t tests were used for statistical comparisons between 2 groups. *P < 0.05. (E) Litter intervals of female mice. Data are presented as mean ± SD. n = 5. Two-tailed Student’s t tests were used for statistical comparisons between 2 groups. ***P < 0.001. (F) Representative images (left) and statistical analysis (right) of ovaries from 2-month-old female mice. Scale bar, 1 mm. Data are presented as mean ± SD. n = 6. Two-tailed Student’s t tests were used for statistical comparisons between 2 groups. *P < 0.05. (G) Representative images (left) and statistical analysis (left) of ovaries from 12-month-old female mice. Scale bar, 1 mm. Data are presented as mean ± SD, n = 4. Two-tailed Student’s t tests were used for statistical comparisons between 2 groups. *P < 0.05.