Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation
| Autor: | Anna Zachariou, Esther Uijttewaal, Shawn Yost, Richarda M. de Voer, Susan Picton, Bas de Wolf, Anna Elliott, Chiara Marcozzi, Sarah F. Smithson, Gunnar Houge, Elise Ruark, Sandra Hanks, Emma Ramsay, Harriet Wylie, Jonathon Pines, Sheila Seal, Nazneen Rahman, Matthew Clarke, Banafsheh Etemad, Geert J. P. L. Kops, Audrey Smith |
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| Přispěvatelé: | Hubrecht Institute for Developmental Biology and Stem Cell Research |
| Rok vydání: | 2017 |
| Předmět: |
Myeloid
0301 basic medicine Microcephaly Developmental Disabilities RNA Stability Aneuploidy Cell Cycle Proteins medicine.disease_cause Neoplasms Multiple Primary Multiple Primary Neoplasms Chromosome Segregation Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] Child Exome sequencing Ovarian Neoplasms Genetics Mutation Leukemia Mosaicism Nuclear Proteins DNA Neoplasm Protein-Serine-Threonine Kinases Kidney Neoplasms Leukemia Myeloid Acute Child Preschool Female Microtubule-Associated Proteins Acute Protein Serine-Threonine Kinases Biology BUB1B Wilms Tumor Article Sertoli-Leydig Cell Tumor 03 medical and health sciences Seizures Journal Article medicine Humans Genetic Predisposition to Disease Preschool Chromosome Wilms' tumor DNA medicine.disease 030104 developmental biology Cancer research Neoplasm ATPases Associated with Diverse Cellular Activities M Phase Cell Cycle Checkpoints Carrier Proteins Carcinogenesis |
| Zdroj: | Nature Genetics, 49, 7, pp. 1148-1151 Nature Genetics, 49, 1148-1151 Nature Genetics, 49(7), 1148-1151. Nature Publishing Group |
| ISSN: | 1061-4036 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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