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 4

Transcriptomic alterations in Helb+/D112Y ovaries.

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Transcriptomic alterations in Helb+/D112Y ovaries. (A) Volcano plot show...
(A) Volcano plot showing differentially expressed genes in ovaries from Helb+/D112Y mice compared with Helb+/+ mice at 2 months old. Genes with P < 0.05 were marked as red [log2 (fold-change) > 1)] or green [log2 (fold-change) < 1]. (B) GO analysis of downregulated genes in Helb+/D112Y mice compared with Helb+/+ mice. (C) The relative mRNA expression levels of Amh, Fshr, Cyp11a1, Cyp17a1, Star, and Hsd3b2 in ovaries from Helb+/+ and Helb+/D112Y mice at 2 months old measured by RT-qPCR and normalized to Gapdh expression. Data are represented as mean ± SD. n = 4. Two-tailed Student’s t tests were used for statistical comparisons between 2 groups. *P < 0.05; ***P < 0.001. (D) The relative mRNA expression levels of Mki67, Cdkn2a, Cdkn1a, Tp53, Il1a, Il1b, and Il6 in the ovaries from Helb+/+ and Helb+/D112Y mice at 12 months old measured by RT-qPCR and normalized to Gapdh expression. Data are represented as mean ± SD. n = 4. Two-tailed Student’s t tests were used for statistical comparisons between 2 groups. *P < 0.05; **P < 0.01; ***P < 0.001.