Mutations resulting in loss of TRIP13 expression induce chromosome missegregation and SAC impairment.
Major finding: Mutations resulting in loss of TRIP13 expression induce chromosome missegregation and SAC impairment.
Clinical relevance:BUB1B or TRIP13 mutations may increase the risk of cancer in patients with mosaic variegated aneuploidy.
Impact: The mechanism by which aneuploidy is generated may determine the risk of cancer.
Mosaic variegated aneuploidy (MVA) syndrome is a rare disorder characterized by constitutional mosaic aneuploidies, microcephaly, developmental delay, and seizures, and is associated with an increased risk of childhood cancer, especially Wilms tumor and rhabdomyosarcoma. Biallelic mutations in the spindle assembly checkpoint (SAC) gene BUB1B or the centrosomal protein gene CEP57 have been linked to MVA, but these mutations are responsible for only a proportion of MVA cases. Yost, de Wolf, Hanks, and colleagues performed exome sequencing of 43 individuals with MVA to identify additional MVA-related genes. A biallelic mutation in TRIP13 (c.1060C>T_p.Arg354X), which encodes a highly conserved AAA+ ATPase that inactivates the SAC effector MAD2, was discovered in 3 patients and prevented functional protein expression. All 3 patients were of Asian origin, had Wilms tumor, and had constitutional mosaic aneuploidies. Exome sequencing of 11 more individuals of Asian origin with Wilms tumor identified 2 additional patients with this mutation, and a Norwegian patient with Wilms tumor was found to have a different truncating TRIP13 mutation (c.673-1G>C) but no constitutional mosaic aneuploidies. Altogether, these findings suggest that TRIP13 mutations may predispose to Wilms tumor. In TRIP13-mutant patients, lymphoblasts had high levels of chromosome segregation errors and could escape mitotic arrest despite unattached chromosomes, indicating SAC impairment. TRIP13 mutations reduced MAD2 recruitment to unattached kinetochores and resulted in SAC deficiency and chromosomal instability. Further, patient cells with TRIP13 or BUB1B mutations had a severely compromised SAC and rapidly escaped from mitotic arrest. Notably, CEP57 mutations are not associated with embryonal tumors and did not result in a compromised SAC. The finding that biallelic TRIP13 mutations predispose to Wilms tumor provides insight into the link between aneuploidy and cancer and suggests that the mechanism underlying aneuploidy may determine the risk of cancer. Further, these data indicate that SAC impairment may underlie the risk of cancer in patients with MVA.
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