Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy

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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 Blanco, 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 Sabater Molina, María
• dc.contributor.author Barriales-Villa, Roberto
• dc.contributor.author Frisso, Giulia
• dc.contributor.author Sancho, Javier
• dc.contributor.author Serrano Pubull, Luis, 1982-
• dc.contributor.author García-Pavía, Pablo
• dc.contributor.author Monserrat, Lorenzo
• dc.contributor.author Alegre-Cebollada, Jorge
• dc.date.accessioned 2021-11-23T06:55:57Z
• dc.date.available 2021-11-23T06:55:57Z
• dc.date.issued 2021
• 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.
• dc.description.sponsorship 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 (SEV-2015-0505). 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 (PIREPRED-EFA086/15). 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.
• dc.format.mimetype application/pdf
• dc.identifier.citation Suay-Corredera C, Pricolo MR, Herrero-Galán E, Velázquez-Carreras D, Sánchez-Ortiz D, García-Giustiniani D, Delgado J, Galano-Frutos JJ, García-Cebollada H, Vilches S, Domínguez F, Molina MS, Barriales-Villa R, Frisso G, Sancho J, Serrano L, García-Pavía P, Monserrat L, Alegre-Cebollada J. Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy. J Biol Chem. 2021;297(1):100854. DOI: 10.1016/j.jbc.2021.100854
• dc.identifier.doi http://dx.doi.org/10.1016/j.jbc.2021.100854
• dc.identifier.issn 0021-9258
• dc.identifier.uri http://hdl.handle.net/10230/49039
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof J Biol Chem. 2021;297(1):100854
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BIO2014-54768-P
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BIO2017-83640-P
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2015-63571-P
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BES-2016-076638
• dc.rights © 2021 The Authors. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.keyword CD
• dc.subject.keyword Alternative splicing
• dc.subject.keyword Bioinformatics
• dc.subject.keyword Cardiac myosin-binding protein C
• dc.subject.keyword Hypertrophic cardiomyopathy
• dc.subject.keyword Minigene
• dc.subject.keyword Protein stability
• dc.subject.keyword Variants of uncertain significance
• dc.title Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion