Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation.
Nat Genet
; 49(7): 1148-1151, 2017 Jul.
Article
en En
| MEDLINE
| ID: mdl-28553959
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Portadoras
/
Tumor de Wilms
/
Segregación Cromosómica
/
Puntos de Control de la Fase M del Ciclo Celular
/
Neoplasias Renales
Límite:
Child, preschool
/
Female
/
Humans
Idioma:
En
Revista:
Nat Genet
Asunto de la revista:
GENETICA MEDICA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Reino Unido