MEI4 variations drive female reproductive disorders via impaired oocyte abundance and developmental potential

Meiotic DNA double-strand break (DSB) formation is pivotal for oocyte development, regulating both ovarian reserve and oocyte developmental potential. Mutations in DSB formation genes have been associated with premature ovarian insufficiency (POI) and adverse pregnancy outcomes in women. Whole exome sequencing in 1530 POI patients across two Chinese cohorts identifies loss-of-function variants in the DSB formation gene, MEI4, enriched in POI. These MEI4 variants impair DSB formation in vitro and reveal a previously unrecognized function of the MEI4 C-terminus in stabilizing the MEI4-REC114 subcomplex on the chromosome axes. Additionally, Mei4^{Arg356∗/Arg356∗} mice display severe defects in DSB formation, leading to massive apoptosis in oocytes triggered by the HORMAD1-dependent synapsis checkpoint in late prophase I. The few mutant oocytes surviving past the checkpoint exhibit low developmental potential, characterized by complete early embryonic arrest due to aneuploidy. Notably, heterozygous Mei4^+/Arg356∗ mice show intermediate follicle depletion and embryonic development arrest consistent with the phenotype of heterozygous POI and preimplantation embryonic arrest, suggesting a haploinsufficiency effect. This study defines the impacts of MEI4 mutation on oocyte quantity and quality, which can guide genetic diagnosis and intervention in patients with POI and early embryonic arrest, especially those with mutations in meiotic DSB formation genes.