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 non-truncating MYBPC3 variants that we classified as HCM-linked or non-pathogenic 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 non-truncating 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.

Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy / Suay-Corredera, Carmen; Pricolo, Maria Rosaria; Herrero-Galán, Elías; Velázquez-Carreras, Diana; Sánchez-Ortiz, David; García-Giustiniani, Diego; Delgado, Javier; Galano-Frutos, Juan José; García-Cebollada, Helena; Vilches, Silvia; Domínguez, Fernando; Molina, María Sabater; Barriales-Villa, Roberto; Frisso, Giulia; Sancho, Javier; Serrano, Luis; García-Pavía, Pablo; Monserrat, Lorenzo; Alegre-Cebollada, Jorge. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - 297:1(2021). [10.1016/j.jbc.2021.100854]

Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy

Pricolo, Maria Rosaria;Frisso, Giulia;
2021

Abstract

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 non-truncating MYBPC3 variants that we classified as HCM-linked or non-pathogenic 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 non-truncating 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
Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy / Suay-Corredera, Carmen; Pricolo, Maria Rosaria; Herrero-Galán, Elías; Velázquez-Carreras, Diana; Sánchez-Ortiz, David; García-Giustiniani, Diego; Delgado, Javier; Galano-Frutos, Juan José; García-Cebollada, Helena; Vilches, Silvia; Domínguez, Fernando; Molina, María Sabater; Barriales-Villa, Roberto; Frisso, Giulia; Sancho, Javier; Serrano, Luis; García-Pavía, Pablo; Monserrat, Lorenzo; Alegre-Cebollada, Jorge. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - 297:1(2021). [10.1016/j.jbc.2021.100854]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/854009
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