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oai:repisalud.isciii.es:20.500.12105/151692024-11-29T09:15:40Zcom_20.500.12105_19604com_20.500.12105_2051com_20.500.12105_15322col_20.500.12105_19605col_20.500.12105_16973col_20.500.12105_16985

00925njm 22002777a 4500 dc Suay-Corredera, Carmen author Pricolo, Maria Rosaria author Herrero-Galán, Elías author Velázquez-Carreras, Diana author Sánchez-Ortiz, David author García-Giustiniani, Diego author Delgado, Javier author Galano-Frutos, Juan José author García-Cebollada, Helena author Vilches, Silvia author Domínguez, Fernando author Molina, María Sabater author Barriales-Villa, Roberto author Frisso, Giulia author Sancho, Javier author Serrano, Luis author García-Pavía, Pablo author Monserrat, Lorenzo author Alegre-Cebollada, Jorge author 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. J Biol Chem. 2021 Jul;297(1):100854 10.1016/j.jbc.2021.100854 1083-351X J Biol Chem http://hdl.handle.net/20.500.12105/15169 Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy.