Ghada M H Abdel-Salam, Susanne Hellmuth, Elise Gradhand, Stephan Käseberg, Jennifer Winter, Ann-Sophie Pabst, Maha M Eid, Holger Thiele, Peter Nürnberg, Birgit S Budde, Mohammad Reza Toliat, Ines B Brecht, Christopher Schroeder, Axel Gschwind, Stephan Ossowski, Friederike Häuser, Heidi Rossmann, Mohamed S Abdel-Hamid, Ibrahim Hegazy, Ahmed G Mohamed, Dominik T Schneider, Aida M Bertoli-Avella, Peter Bauer, Jillian N Pearring, Rolph Pfundt, Alexander Hoischen, Christian Gilissen, Dennis Strand, Ulrich Zechner, Soha A Tashkandi, Eissa A Faqeih, Olaf Stemmann, Susanne Strand, Hanno J Bolz
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...
October 5, 2023: JCI Insight