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Biallelic MAD2L1BP (p31comet) mutation is associated with mosaic aneuploidy and juvenile granulosa cell tumors
Ghada M. H. Abdel-Salam, … , Susanne Strand, Hanno J. Bolz
Ghada M. H. Abdel-Salam, … , Susanne Strand, Hanno J. Bolz
Published October 5, 2023
Citation Information: JCI Insight. 2023;8(22):e170079. https://doi.org/10.1172/jci.insight.170079.
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Research Article Genetics Oncology

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

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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 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.

Authors

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

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Figure 1

Clinical phenotype of family 1 patients.

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Clinical phenotype of family 1 patients.
(A–J) Patient 1a. (A and B) Mil...
(A–J) Patient 1a. (A and B) Mild facial dysmorphism (4 years): long face, upward slanting sparse outer eyebrows, low columella, pointed chin, and microcephaly. (C) Fundus: retinal pigmentation defects. (D) Cranial MRI (cMRI) (24 months): underdeveloped brain with dysplastic frontal lobe, interhemispheric cyst, and polymicrogyria on the right near the cyst. Incomplete opercularization and left parietal cyst. (E–J) Histology of ovarian GCT. (E–G) H&E staining shows the faint preserved outlines of the macrofollicular architecture. Regressive calcification is visible in C. (H and I) Reticulin stains the preserved fibers, highlighting the typical and unique architecture for JGCT; E, at higher magnification. (J) Periodic acid–Schiff (PAS) staining shows the typical cytology of the JGCT with monomorphic, round to ovoid cells. (K–U) Patient 1b. (K and L) Face with mild dysmorphism (2 years of age). (M) Ultrasound image of left testicular mass. (N) Thin corpus callosum (cMRI at the age of 18 months). (O–U) Histology of testicular GCT. (O) Testis shows a macrofollicular pattern and contains multiple cysts replacing preexisting prepubertal testicular tissue. (P) Multilayered tumor cells surrounded by spindle cell stroma, reminiscent of ovarian follicles. (Q) Cysts contain pink mucoid material. The cells of the inner layer are pale and have luteinized cytoplasm. (R) Tumor cells show progesterone receptor (PR) expression. (S) Tumor cells with diffuse S100 expression. (T) Faint expression of estrogen receptor (ER). (U) Patchy expression of inhibin. (E, F, H, and O) Original magnification, 2×; scale bar: 500 μm. (G, I, S, and T) Original magnification, 4×; scale bar: 300 μm. (J, P, and Q) Original magnification, 10×, scale bar: 100 μm. (R and U) Original magnification, 40×, scale bar: 50 μm.

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