JCI Insight (Nov 2023)

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

  • 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 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

Journal volume & issue
Vol. 8, no. 22

Abstract

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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 2 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 an 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.

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