Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation
| العنوان: | Biallelic TRIP13 mutations predispose to Wilms tumor and chromosome missegregation |
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| المؤلفون: | 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 |
| المساهمون: | Hubrecht Institute for Developmental Biology and Stem Cell Research |
| المصدر: | Nature Genetics, 49, 7, pp. 1148-1151 Nature Genetics, 49, 1148-1151 Nature Genetics, 49(7), 1148-1151. Nature Publishing Group |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| وصف الملف: | image/pdf |
| تدمد: | 1061-4036 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6242b84b6ea9ef95284c06180fd1173b https://doi.org/10.1038/ng.3883 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....6242b84b6ea9ef95284c06180fd1173b |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 10614036 |
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