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 1

Identification of a deleterious variant of HELB in a Chinese family with POI and early menopause.

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Identification of a deleterious variant of HELB in a Chinese family with...
(A) A heterozygous missense variant (M) c.349G>T (p.Asp117Tyr) of HELB was identified in a Chinese family with POI and early menopause. The black-filled symbol indicates the proband with POI, and gray-filled symbols represent family members affected with early menopause. (B) Flowchart of WES filtering strategies based on quality, frequency, deleteriousness, and biological significance. Filters include quality (variants with high/medium calling quality: sequencing depth > 30, genotype quality > 30, no low-quality calls); coding (exonic or splice site variants); Freq (minor allele frequencies < 0.001 in the 1000 Genomes Project [1000g], gnomAD, and ExAC databases); score (variants predicted to be damaging by SIFT, PolyPhen-2, MutationTaster, and CADD_phred > 25); and shared (variants shared by III-1 and II-1). (C) Sanger sequencing confirmation of the HELB variants in affected individuals. The mutated positions are highlighted in yellow. (D) Schematic representation of human genomic HELB (NM_033647.5) and human HELB protein (NP_387467.2). The mutated positions are indicated by red dots. (E) Conservation analysis of HELB amino acid residues across species. The red arrow indicates the Asp117 residue affected by the identified variant.