Biallelic MAD2L1BP (p31comet) mutation is associated with mosaic aneuploidy and juvenile granulosa cell tumors

MAD2L1BP-encoded p31comet mediates Trip13-dependent disassembly of Mad2- and Rev7-containing complexes and, through this antagonism, promotes timely spindle assembly checkpoint (SAC) silencing, faithful chromosome segregation, insulin signaling and homology-directed repair (HDR) of DNA double-strand breaks. We identified a homozygous MAD2L1BP nonsense variant, R253*, in two siblings with microcephaly, epileptic encephalopathy and juvenile granulosa cell tumors of ovary and testis. Patient-derived cells exhibited high-grade mosaic variegated aneuploidy, slowed-down proliferation, and instability of truncated p31comet mRNA and protein. Corresponding recombinant p31comet was defective in Trip13-, Mad2- and Rev7-binding and unable to support SAC silencing or HDR. Furthermore, C-terminal truncation abrogated a newly identified interaction of p31comet with tp53. Another homozygous truncation, R227*, detected in an early deceased patient with low-level aneuploidy, severe epileptic encephalopathy and frequent blood glucose elevations likely corresponds to complete loss-of-function, as in Mad2l1bp–/– mice. Thus, human mutations of p31comet are linked to aneuploidy and tumor predisposition.