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dc.contributor.author | Suay-Corredera, Carmen | |
dc.contributor.author | Pricolo, Maria Rosaria | |
dc.contributor.author | Herrero-Galán, Elías | |
dc.contributor.author | Velázquez-Carreras, Diana | |
dc.contributor.author | Sánchez-Ortiz, David | |
dc.contributor.author | García-Giustiniani, Diego | |
dc.contributor.author | Delgado, Javier | |
dc.contributor.author | Galano-Frutos, Juan José | |
dc.contributor.author | García-Cebollada, Helena | |
dc.contributor.author | Vilches, Silvia | |
dc.contributor.author | Domínguez, Fernando | |
dc.contributor.author | Molina, María Sabater | |
dc.contributor.author | Barriales-Villa, Roberto | |
dc.contributor.author | Frisso, Giulia | |
dc.contributor.author | Sancho, Javier | |
dc.contributor.author | Serrano, Luis | |
dc.contributor.author | García-Pavía, Pablo | |
dc.contributor.author | Monserrat, Lorenzo | |
dc.contributor.author | Alegre-Cebollada, Jorge | |
dc.date.accessioned | 2022-11-16T14:05:32Z | |
dc.date.available | 2022-11-16T14:05:32Z | |
dc.date.issued | 2021 | |
dc.identifier.citation | J Biol Chem. 2021 Jul;297(1):100854 | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/15169 | |
dc.description.abstract | Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. Variants in MYBPC3, the gene encoding cardiac myosin-binding protein C (cMyBP-C), are the leading cause of HCM. However, the pathogenicity status of hundreds of MYBPC3 variants found in patients remains unknown, as a consequence of our incomplete understanding of the pathomechanisms triggered by HCM-causing variants. Here, we examined 44 nontruncating MYBPC3 variants that we classified as HCM-linked or nonpathogenic according to cosegregation and population genetics criteria. We found that around half of the HCM-linked variants showed alterations in RNA splicing or protein stability, both of which can lead to cMyBP-C haploinsufficiency. These protein haploinsufficiency drivers associated with HCM pathogenicity with 100% and 94% specificity, respectively. Furthermore, we uncovered that 11% of nontruncating MYBPC3 variants currently classified as of uncertain significance in ClinVar induced one of these molecular phenotypes. Our strategy, which can be applied to other conditions induced by protein loss of function, supports the idea that cMyBP-C haploinsufficiency is a fundamental pathomechanism in HCM. | es_ES |
dc.description.sponsorship | Funding and additional information—J. A.-C. acknowledges funding from the Ministerio de Ciencia e Innovación (MCIN) through grants BIO2014-54768-P; BIO2017-83640-P/MINECO/AEI/ FEDER, UE; EIN2019-102966 and RYC-2014-16604, the European Research Area Network on Cardiovascular Diseases (ERA-CVD/ ISCIII, Spain MINOTAUR, AC16/00045), and the Comunidad de Madrid (consortium Tec4Bio-CM, S2018/NMT-4443, FEDER). The CNIC is supported by the ISCIII, MCIN, and the Pro CNIC Foundation and was a Severo Ochoa Center of Excellence (SEV2015-0505). We acknowledge funding from ISCIII to the Centro de Investigación Biomédica en Red (CB16/11/00425). L. S. acknowledges funding from MCIN (BFU2015-63571-P). J. S. acknowledges funding from AEI (PID2019-107293GB-I00), Gobierno de Aragón (E45_17R), and ERDF-InterregV-A POCTEFA, Spain (PIREPREDEFA086/15). C. S.-C. is the recipient of an FPI-SO predoctoral fellowship BES-2016-076638. M. R. P. was the recipient of a PhD fellowship from the Italian Ministry of Education, Universities and Research, Italy. H. G.-C. is the recipient of an FPU16/04232 doctoral contract from MCIN. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | American Society of Biological Chemists | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | * |
dc.subject.mesh | Cardiomyopathy, Hypertrophic | es_ES |
dc.subject.mesh | Carrier Proteins | es_ES |
dc.subject.mesh | Cytoskeletal Proteins | es_ES |
dc.subject.mesh | Female | es_ES |
dc.subject.mesh | Haploinsufficiency | es_ES |
dc.subject.mesh | Humans | es_ES |
dc.subject.mesh | Male | es_ES |
dc.subject.mesh | Molecular Dynamics Simulation | es_ES |
dc.subject.mesh | Mutation | es_ES |
dc.subject.mesh | Phenotype | es_ES |
dc.subject.mesh | RNA Splicing | es_ES |
dc.title | Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy. | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Atribución 4.0 Internacional | * |
dc.identifier.doi | 10.1016/j.jbc.2021.100854 | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación (España) | es_ES |
dc.contributor.funder | European Research Area Network on Cardiovascular Diseases | es_ES |
dc.contributor.funder | Comunidad de Madrid (España) | es_ES |
dc.contributor.funder | Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) | es_ES |
dc.contributor.funder | Instituto de Salud Carlos III | es_ES |
dc.contributor.funder | Fundación ProCNIC | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España) | es_ES |
dc.contributor.funder | Centro de Investigación Biomédica en Red - CIBERCV (Enfermedades Cardiovasculares) | es_ES |
dc.contributor.funder | Gobierno de Aragón (España) | es_ES |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 1083-351X | es_ES |
dc.relation.publisherversion | 10.1016/j.jbc.2021.100854 | es_ES |
dc.identifier.journal | J Biol Chem | es_ES |
dc.repisalud.orgCNIC | CNIC::Grupos de investigación::Mecánica molecular del sistema cardiovascular | es_ES |
dc.repisalud.institucion | CNIC | es_ES |
dc.rights.accessRights | open access | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/BIO2014-54768-P | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/BIO2017-83640-P | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/EIN2019-102966 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/RYC-2014-16604 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/AC16/00045 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/S2018/NMT-4443 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/SEV2015-0505 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/CB16/11/00425 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/BFU2015-63571-P | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2019-107293GB-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PIREPREDEFA086/15 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/BES-2016-076638 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/FPU16/04232 | es_ES |