130806 20240131210811.0 doi 10.1016/j.jbc.2021.100854 sideral 126576 ART-2021-126576 eng Suay-Corredera C. Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy 2021 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. © 2021 THE AUTHORS. Access copy available to the general public Unrestricted info:eu-repo/semantics/openAccess by http://creativecommons.org/licenses/by/3.0/es/ 5.485 2021 BIOCHEMISTRY & MOLECULAR BIOLOGY 94 / 297 = 0.316 2021 Q2 T1 1.871 2021 Cell Biology 2021 Q1 Biochemistry 2021 Q1 8.8 2021 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Pricolo M.R. Herrero-Galán E. Velázquez-Carreras D. Sánchez-Ortiz D. García-Giustiniani D. Delgado J. Galano-Frutos J.J. (orcid)0000-0002-1896-7805 García Cebollada H. Universidad de Zaragoza (orcid)0000-0002-9590-7371 Vilches S. Domínguez F. Molina M.S. Barriales-Villa R. Frisso G. Sancho Sanz J. Universidad de Zaragoza (orcid)0000-0002-2879-9200 Serrano L. García-Pavía P. Monserrat L. Alegre-Cebollada J. 1002 060 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Bioquímica y Biolog.Mole. 297, 1 (2021), 100854 [14 pp] J. biol. chem. Journal of Biological Chemistry 0021-9258 1943293 http://zaguan.unizar.es/record/130806/files/texto_completo.pdf Versión publicada 3623000 http://zaguan.unizar.es/record/130806/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:130806 articulos driver 2024-01-31-19:22:55 ARTICLE