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Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation.

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Accepted version (553.6Kb)
Date
2017-07
ICR Author
Pines, Jonathon
Rahman, Sabera
Author
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
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Type
Journal Article
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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.
URI
https://repository.icr.ac.uk/handle/internal/884
DOI
https://doi.org/10.1038/ng.3883
Collections
  • Breast Cancer Research
  • Genetics and Epidemiology
Subject
Humans
Sertoli-Leydig Cell Tumor
Ovarian Neoplasms
Kidney Neoplasms
Neoplasms, Multiple Primary
Microcephaly
Seizures
Aneuploidy
Genetic Predisposition to Disease
Protein-Serine-Threonine Kinases
Carrier Proteins
Cell Cycle Proteins
Microtubule-Associated Proteins
Nuclear Proteins
DNA, Neoplasm
Developmental Disabilities
Chromosome Segregation
RNA Stability
Mutation
Mosaicism
Child, Preschool
Female
Wilms Tumor
Leukemia, Myeloid, Acute
M Phase Cell Cycle Checkpoints
ATPases Associated with Diverse Cellular Activities
Research team
Genetic Susceptibility
Language
eng
Date accepted
2017-05-01
License start date
2017-07
Citation
Nature genetics, 2017, 49 (7), pp. 1148 - 1151

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