Biallelic Variants inMAD2L1BP(p31^comet) Cause Female Infertility Characterized by Oocyte Maturation Arrest

Human oocyte maturation arrest represents one of the severe conditions for female patients with primary infertility. However, the genetic factors underlying this human disease remain largely unknown. The spindle assembly checkpoint (SAC) is an intricate surveillance mechanism that ensures accurate segregation of chromosomes throughout cell cycles. Once the kinetochores of chromosomes are correctly attached to bipolar spindles and the SAC is satisfied, the MAD2L1BP, best known asp31^comet, binds MAD2 and recruits the AAA+-ATPase TRIP13 to disassemble the mitotic checkpoint complex (MCC), leading to the cell cycle progression. In this study, by whole-exome sequencing (WES), we identified homozygous and compound heterozygousMAD2L1BPvariants in three families with female patients diagnosed with primary infertility owing to oocyte metaphase I (MI) arrest. Functional studies revealed that the protein variants resulting from the C-terminal truncation of MAD2L1BP lost their binding ability to MAD2. cRNA microinjection of full-length or truncated MAD2L1BP uncovered their discordant roles in driving the extrusion of polar body 1 (PB1) in mouse oocytes. Furthermore, the patient’s oocytes carrying the mutatedMAD2L1BPvariants resumed polar body extrusion (PBE) when rescued by microinjection of full-lengthMAD2L1BPcRNAs. Together, our studies identified and characterized novel biallelic variants inMAD2L1BPresponsible for human oocyte maturation arrest at MI, and thus prompted new therapeutic avenues for curing female primary infertility.