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

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Abdel-Salam, Ghada M. H. ; Hellmuth, Susanne ; Gradhand, Elise ; Käseberg, Stephan ; Winter, Jennifer ; Pabst, Ann-Sophie ; Eid, Maha M. ; Thiele, Holger ; Nürnberg, Peter ; Budde, Birgit S. ; Toliat, Mohammad Reza ; Brecht, Ines B. ; Schroeder, Christopher ; Gschwind, Axel ; Ossowski, Stephan ; Häuser, Friederike ; Rossmann, Heidi ; Abdel-Hamid, Mohamed S. ; Hegazy, Ibrahim ; Mohamed, Ahmed G. ; Schneider, Dominik T. ; Bertoli-Avella, Aida M. ; Bauer, Peter ; Pearring, Jillian N. ; Pfundt, Rolph ; Hoischen, Alexander ; Gilissen, Christian ; Strand, Dennis ; Zechner, Ulrich ; Tashkandi, Soha A. ; Faqeih, Eissa A. ; Stemmann, Olaf ; Strand, Susanne ; Bolz, Hanno J.:
Biallelic MAD2L1BP (p31ᶜᵒᵐᵉᵗ) mutation is associated with mosaic aneuploidy and juvenile granulosa cell tumors.
In: JCI Insight. Bd. 8 (2023) Heft 22 . - e170079.
ISSN 2379-3708
DOI: https://doi.org/10.1172/jci.insight.170079

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Abstract

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.