期刊
NATURE COMMUNICATIONS
卷 6, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms9383
关键词
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资金
- Spanish Ministry of Health [PI12/00070, PI11/0699, PI12/01941, RD12/0042/0066]
- Spanish Ministry of Science and Innovation (INNPRONTA)
- Spanish Research Network on Rare diseases (CIBERER)
- CIBERER
- FEDER funds [PI12/00070, PI11/0949]
- Spanish Ministry of Science and Innovation [SAF2008-05384, 2007-A-200950]
- European Research Council [232854]
- Korber Foundation
- Fundacion Botin
- Fundacion Lilly
- ICREA Funding Source: Custom
Cardiac angiosarcoma (CAS) is a rare malignant tumour whose genetic basis is unknown. Here we show, by whole-exome sequencing of a TP53-negative Li-Fraumeni-like (LFL) family including CAS cases, that a missense variant (p.R117C) in POT1 (protection of telomeres 1) gene is responsible for CAS. The same gene alteration is found in two other LFL families with CAS, supporting the causal effect of the identified mutation. We extend the analysis to TP53-negative LFL families with no CAS and find the same mutation in a breast AS family. The mutation is recently found once in 121,324 studied alleles in ExAC server but it is not described in any other database or found in 1,520 Spanish controls. In silico structural analysis suggests how the mutation disrupts POT1 structure. Functional and in vitro studies demonstrate that carriers of the mutation show reduced telomere-bound POT1 levels, abnormally long telomeres and increased telomere fragility.
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