Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation

A partir d'échantillons prélevés sur 6 patients atteints d'un néphroblastome, cette étude met en évidence une association entre des mutations bialléliques du gène TRIP13, une aneuploïdie et le risque de développer la maladie

Résumé en anglais

Through exome sequencing, we identified six individuals with biallelic loss-of-function mutations in TRIP13. All six developed Wilms tumor. Constitutional mosaic aneuploidies, microcephaly, developmental delay and seizures, which are features of mosaic variegated aneuploidy (MVA) syndrome1, 2, were more variably present. Through functional studies, we show that TRIP13-mutant patient cells have no detectable TRIP13 and have substantial impairment of the spindle assembly checkpoint (SAC), leading to a high rate of chromosome missegregation. Accurate segregation, as well as SAC proficiency, is rescued by restoring TRIP13 function. Individuals with biallelic TRIP13 or BUB1B mutations have a high risk of embryonal tumors3, and here we show that their cells display severe SAC impairment. MVA due to biallelic CEP57 mutations4, or of unknown cause, is not associated with embryonal tumors and cells from these individuals show minimal SAC deficiency. These data provide insights into the complex relationships between aneuploidy and carcinogenesis