Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation.
Loading...
Embargo End Date
ICR Authors
Authors
Yost, S
de Wolf, B
Hanks, S
Zachariou, A
Marcozzi, C
Clarke, M
de Voer, R
Etemad, B
Uijttewaal, E
Ramsay, E
Wylie, H
Elliott, A
Picton, S
Smith, A
Smithson, S
Seal, S
Ruark, E
Houge, G
Pines, J
Kops, GJPL
Rahman, N
de Wolf, B
Hanks, S
Zachariou, A
Marcozzi, C
Clarke, M
de Voer, R
Etemad, B
Uijttewaal, E
Ramsay, E
Wylie, H
Elliott, A
Picton, S
Smith, A
Smithson, S
Seal, S
Ruark, E
Houge, G
Pines, J
Kops, GJPL
Rahman, N
Document Type
Journal Article
Date
2017-07-01
Date Accepted
2017-05-01
Abstract
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) syndrome, 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 tumors, and here we show that their cells display severe SAC impairment. MVA due to biallelic CEP57 mutations, 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.
Citation
Nature genetics, 2017, 49 (7), pp. 1148 - 1151
DOI
Source Title
Publisher
NATURE PORTFOLIO
ISSN
1061-4036
eISSN
1546-1718
Research Team
Genetic Susceptibility