Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy.

Autor:	Suay-Corredera C; Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain., Pricolo MR; Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy., Herrero-Galán E; Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain., Velázquez-Carreras D; Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain., Sánchez-Ortiz D; Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain., García-Giustiniani D; Health in Code, A Coruña, Spain., Delgado J; EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain., Galano-Frutos JJ; Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, Spain; Biocomputation and Complex Systems Physics Institute (BIFI). Joint Units BIFI-IQFR (CSIC) and GBs-CSIC, Universidad de Zaragoza, Zaragoza, Spain., García-Cebollada H; Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, Spain; Biocomputation and Complex Systems Physics Institute (BIFI). Joint Units BIFI-IQFR (CSIC) and GBs-CSIC, Universidad de Zaragoza, Zaragoza, Spain., Vilches S; Heart Failure and Inherited Cardiac Diseases Unit. Department of Cardiology. Hospital Universitario Puerta de Hierro, Madrid, Spain; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-HEART), Madrid, Spain., Domínguez F; Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Heart Failure and Inherited Cardiac Diseases Unit. Department of Cardiology. Hospital Universitario Puerta de Hierro, Madrid, Spain; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-HEART), Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain., Molina MS; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-HEART), Madrid, Spain; Hospital C. Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain., Barriales-Villa R; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Unidad de Cardiopatías Familiares, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña, Servizo Galego de Saúde (SERGAS), Universidade da Coruña, A Coruña, Spain., Frisso G; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy; CEINGE Biotecnologie Avanzate, scarl, Naples, Italy., Sancho J; Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, Spain; Biocomputation and Complex Systems Physics Institute (BIFI). Joint Units BIFI-IQFR (CSIC) and GBs-CSIC, Universidad de Zaragoza, Zaragoza, Spain; Aragon Health Research Institute (IIS Aragón), Zaragoza, Spain., Serrano L; EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain., García-Pavía P; Heart Failure and Inherited Cardiac Diseases Unit. Department of Cardiology. Hospital Universitario Puerta de Hierro, Madrid, Spain; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-HEART), Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcón, Madrid, Spain., Monserrat L; Health in Code, A Coruña, Spain., Alegre-Cebollada J; Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. Electronic address: jalegre@cnic.es.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2021 Jul; Vol. 297 (1), pp. 100854. Date of Electronic Publication: 2021 Jun 05.
DOI:	10.1016/j.jbc.2021.100854
Abstrakt:	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. Competing Interests: Conflict of interest L. M. holds share in Health in Code. All other authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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