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dc.contributor.author | Pricolo, Maria Rosaria | |
dc.contributor.author | Herrero-Galan, Elas | |
dc.contributor.author | Mazzaccara, Cristina | |
dc.contributor.author | Losi, Maria Angela | |
dc.contributor.author | Alegre-Cebollada, Jorge | |
dc.contributor.author | Frisso, Giulia | |
dc.date.accessioned | 2020-10-28T09:11:14Z | |
dc.date.available | 2020-10-28T09:11:14Z | |
dc.date.issued | 2020-10 | |
dc.identifier.citation | J Cardiovasc Transl Res. 2020; 13(5):867-877 | es_ES |
dc.identifier.issn | 1937-5387 | |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/11235 | |
dc.description.abstract | In 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.sponsorship | J.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.iso | eng | es_ES |
dc.publisher | Springer | es_ES |
dc.type.hasVersion | AM | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.title | Protein Thermodynamic Destabilization in the Assessment of Pathogenicity of a Variant of Uncertain Significance in Cardiac Myosin Binding Protein C. | es_ES |
dc.type | journal article | es_ES |
dc.rights.license | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.identifier.pubmedID | 32034629 | es_ES |
dc.format.volume | 13 | es_ES |
dc.format.number | 5 | es_ES |
dc.format.page | 867-877 | es_ES |
dc.identifier.doi | 10.1007/s12265-020-09959-6 | es_ES |
dc.contributor.funder | Ministerio de Ciencia, Innovación y Universidades (España) | |
dc.contributor.funder | Comunidad de Madrid (España) | |
dc.contributor.funder | Centro Nacional de Investigaciones Cardiovasculares Carlos III (España) | |
dc.contributor.funder | Instituto de Salud Carlos III | |
dc.contributor.funder | Ministero dell Istruzione (Italia) | |
dc.contributor.funder | Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) | |
dc.contributor.funder | Fundación ProCNIC | |
dc.description.peerreviewed | Sí | es_ES |
dc.relation.publisherversion | https://doi.org/10.1007/s12265-020-09959-6 | es_ES |
dc.identifier.journal | Journal of cardiovascular translational research | es_ES |
dc.repisalud.orgCNIC | CNIC::Grupos de investigación::Mecánica molecular del sistema cardiovascular | es_ES |
dc.repisalud.institucion | CNIC | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/SEV-2015-0505 | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/BIO2017-83640-P | es_ES |
dc.relation.projectID | info:eu-repo/grantAgreement/ES/RYC-2014-16604 | es_ES |
dc.rights.accessRights | open access | es_ES |