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dc.contributor.authorCalvete, Oriol 
dc.contributor.authorMartinez, Paula 
dc.contributor.authorGarcia-Pavia, Pablo 
dc.contributor.authorBenitez-Buelga, Carlos 
dc.contributor.authorPaumard-Hernandez B 
dc.contributor.authorFernandez, Victoria 
dc.contributor.authorDominguez, Fernando 
dc.contributor.authorSalas, Clara
dc.contributor.authorRomero-Laorden, Nuria
dc.contributor.authorGarcia-Donas, Jesus
dc.contributor.authorCarrillo, Jaime
dc.contributor.authorPerona, Rosario
dc.contributor.authorCarlos Trivino, Juan
dc.contributor.authorAndrés, Raquel
dc.contributor.authorMaria Cano, Juana
dc.contributor.authorRivera, Barbara
dc.contributor.authorAlonso-Pulpon, Luis
dc.contributor.authorSetien, Fernando
dc.contributor.authorEsteller, Manel
dc.contributor.authorRodriguez Perales, Sandra 
dc.contributor.authorBougeard, Gaelle
dc.contributor.authorFrebourg, Tierry
dc.contributor.authorUrioste, Miguel 
dc.contributor.authorBlasco, MA 
dc.contributor.authorBenitez, Javier 
dc.date.accessioned2017-11-27T13:49:50Z
dc.date.available2017-11-27T13:49:50Z
dc.date.issued2015
dc.identifierISI:000363136500002
dc.identifier.citationNat Commun. 2015; 6:8383
dc.identifier.issn2041-1723
dc.identifier.urihttp://hdl.handle.net/20.500.12105/5394
dc.description.abstractCardiac 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.
dc.description.sponsorshipWe are grateful to T. de Lange (The Rockefeller University) and K. Collins (The University of California) for providing POT1 and TPP1 plasmids, respectively. J.B.'s laboratory is partially funded by the Spanish Ministry of Health PI12/00070, the Spanish Ministry of Science and Innovation (INNPRONTA 2012) and the Spanish Research Network on Rare diseases (CIBERER). O.C. is granted by the CIBERER and C.B.-B. by the PI12/00070 supported by FEDER funds. P.G.-P. is partially supported by the Spanish Ministry of Health PI11/0699, PI12/01941 and RD12/0042/0066. M.A.B.'s laboratory is funded with the Spanish Ministry of Science and Innovation, projects SAF2008-05384 and 2007-A-200950 (TELOMARKER), European Research Council Advanced grant GA\#232854, the Korber Foundation, Fundacion Botin and Fundacion Lilly. R.P.' lab is partially funded by PI11/0949 Supported by FEDER funds.
dc.language.isoeng
dc.publisherNature Publishing Group 
dc.type.hasVersionVoR
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectTELOMERE LENGTH
dc.subjectQUANTITATIVE PCR
dc.subjectPROTEIN
dc.subjectVARIANTS
dc.subjectREQUIREMENTS
dc.subjectMAINTENANCE
dc.subjectPREDISPOSE
dc.subjectEXPRESSION
dc.subjectPREDICTION
dc.subjectPROTECTION
dc.titleA mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families
dc.typejournal article
dc.rights.licenseAtribución 4.0 Internacional*
dc.identifier.pubmedID26403419
dc.format.volume6
dc.identifier.doi10.1038/ncomms9383
dc.contributor.funderInstituto de Salud Carlos III 
dc.contributor.funderMinisterio de Ciencia e Innovación (España) 
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) 
dc.contributor.funderCentro de Investigación Biomedica en Red - CIBER
dc.contributor.funderUnión Europea. Comisión Europea 
dc.contributor.funderUnión Europea. Comisión Europea. European Research Council (ERC) 
dc.contributor.funderKorber Foundation
dc.contributor.funderBotín Foundation 
dc.contributor.funderFundación Lilly 
dc.contributor.funderICREA
dc.description.peerreviewed
dc.relation.publisherversionhttps://doi.org/10.1038/ncomms9383
dc.identifier.journalNature Communications
dc.repisalud.orgCNICCNIC::Grupos de investigación::Regulación Molecular de la Insuficiencia Cardiaca
dc.repisalud.institucionCNIC
dc.repisalud.institucionCNIO
dc.relation.projectIDinfo:eu-repo/grantAgreement/EC/FP7/232854/EUes_ES
dc.rights.accessRightsopen accesses_ES


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