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dc.contributor.authorPricolo, Maria Rosaria
dc.contributor.authorHerrero-Galan, Elas 
dc.contributor.authorMazzaccara, Cristina
dc.contributor.authorLosi, Maria Angela
dc.contributor.authorAlegre-Cebollada, Jorge 
dc.contributor.authorFrisso, Giulia
dc.date.accessioned2020-10-28T09:11:14Z
dc.date.available2020-10-28T09:11:14Z
dc.date.issued2020-10
dc.identifier.citationJ Cardiovasc Transl Res. 2020; 13(5):867-877es_ES
dc.identifier.issn1937-5387
dc.identifier.urihttp://hdl.handle.net/20.500.12105/11235
dc.description.abstractIn the era of next generation sequencing (NGS), genetic testing for inherited disorders identifies an ever-increasing number of variants whose pathogenicity remains unclear. These variants of uncertain significance (VUS) limit the reach of genetic testing in clinical practice. The VUS for hypertrophic cardiomyopathy (HCM), the most common familial heart disease, constitute over 60% of entries for missense variants shown in ClinVar database. We have studied a novel VUS (c.1809T>G-p.I603M) in the most frequently mutated gene in HCM, MYBPC3, which codes for cardiac myosin-binding protein C (cMyBPC). Our determinations of pathogenicity integrate bioinformatics evaluation and functional studies of RNA splicing and protein thermodynamic stability. In silico prediction and mRNA analysis indicated no alteration of RNA splicing induced by the variant. At the protein level, the p.I603M mutation maps to the C4 domain of cMyBPC. Although the mutation does not perturb much the overall structure of the C4 domain, the stability of C4 I603M is severely compromised as detected by circular dichroism and differential scanning calorimetry experiments. Taking into account the highly destabilizing effect of the mutation in the structure of C4, we propose reclassification of variant p.I603M as likely pathogenic. Looking into the future, the workflow described here can be used to refine the assignment of pathogenicity of variants of uncertain significance in MYBPC3.es_ES
dc.description.sponsorshipJ.A.C. was funded by the Ministerio de Ciencia, Innovación y Universidades (MCNU) through grants BIO2017-83640-P (AEI/FEDER, UE) and RYC-2014-16604, the European Research Area Network on Cardiovascular Diseases (ERA-CVD/ISCIII, MINOTAUR, AC16/00045), the Comunidad de Madrid (P2018/NMT-4443) and the CNIC-Severo Ochoa intramural grant program (03-2016 IGP). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), MCNU and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). G.F. was funded by the Ministero dell’Istruzione, dell’Università e della Ricerca-Rome PS35-126/IND.es_ES
dc.language.isoenges_ES
dc.publisherSpringer es_ES
dc.type.hasVersionAMes_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.titleProtein Thermodynamic Destabilization in the Assessment of Pathogenicity of a Variant of Uncertain Significance in Cardiac Myosin Binding Protein C.es_ES
dc.typejournal articlees_ES
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.identifier.pubmedID32034629es_ES
dc.format.volume13es_ES
dc.format.number5es_ES
dc.format.page867-877es_ES
dc.identifier.doi10.1007/s12265-020-09959-6es_ES
dc.contributor.funderMinisterio de Ciencia, Innovación y Universidades (España) 
dc.contributor.funderComunidad de Madrid (España) 
dc.contributor.funderCentro Nacional de Investigaciones Cardiovasculares Carlos III (España) 
dc.contributor.funderInstituto de Salud Carlos III 
dc.contributor.funderMinistero dell Istruzione (Italia) 
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) 
dc.contributor.funderFundación ProCNIC 
dc.description.peerreviewedes_ES
dc.relation.publisherversionhttps://doi.org/10.1007/s12265-020-09959-6es_ES
dc.identifier.journalJournal of cardiovascular translational researches_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Mecánica molecular del sistema cardiovasculares_ES
dc.repisalud.institucionCNICes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/SEV-2015-0505es_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/BIO2017-83640-Pes_ES
dc.relation.projectIDinfo:eu-repo/grantAgreement/ES/RYC-2014-16604es_ES
dc.rights.accessRightsopen accesses_ES


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Attribution-NonCommercial-NoDerivatives 4.0 Internacional
Este Item está sujeto a una licencia Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 Internacional