Mild defects in follicular development and reproductive performance in the heterozygous Hfm1 female mouse

Helicase for meiosis 1 (HFM1) is an ATP-dependent DNA helicase expressed primarily in the germ cells and plays a conserved role in meiotic synapsis and recombination. Biallelic HFM1 mutations are responsible for female infertility and various forms of pregnancy loss associated with primary ovarian insufficiency (POI), whereas monoallelic HFM1 mutations are found in women with milder forms of reproductive failures. Homozygous null mutation of Hfm1 in the female mouse exhibited severe defects in the meiotic synapsis and crossovers in oocytes, leading to aberrant chromosome segregation at the first meiotic division. However, the Hfm1 null female mouse loses all its oocytes prior to puberty, precluding further studies on the role of HFM1 in female reproduction. In the current study, we examined various fertility parameters in the heterozygous Hfm1 mutant mouse, which did not exhibit aberrant meiotic synapsis or recombination. Our results indicated largely normal ovarian development, consistent with their fertility. Nonetheless, we found (1) mild defects in follicle formation and recruitment, (2) delay in the initial increase in reproductive capacity and faster decline in fertility with age, (3) slower preimplantation development of embryos in culture, and (4) smaller ovarian reserve near the end of the reproductive life, compared to wild-type mice. We suggest that similar defects may underlie the reproductive failure of women with monoallelic HFM1 mutations.