Abstract 471: Exploring Haploinssuficiency Drivers in a Set of cMyBP-C Missense Mutations Causing Hypertrophic Cardiomyopathy
| Autor: | Carmen Suay-Corredera, Luis Serrano, David Sánchez-Ortiz, Diego García-Giustiniani, Roberto Barriales-Villa, Fernando Domínguez, Lorenzo Monserrat, Diana Velázquez-Carreras, Javier Delgado, Pablo García-Pavía, Maria Rosaria Pricolo, Silvia Vilches, Jorge Alegre-Cebollada, Elías Herrero-Galán, Giulia Frisso |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | Circulation Research. 125 |
| ISSN: | 1524-4571 0009-7330 |
| Popis: | Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. Mutations in cardiac myosin-binding protein C (cMyBP-C) are a leading cause of HCM. However, as for many other genetic diseases, it remains challenging to define whether specific gene variants found in patients are pathogenic or not. Here, we have examined pathogenicity drivers in a group of clinically annotated exonic variants of MYBPC3, the gene encoding cMyBP-C. First, we did bioinformatics predictions of RNA splicing and of protein thermodynamic stability. To validate results, we studied RNA splicing of the MYBPC3 gene using peripheral blood from variant carriers, and circular dichroism measurements on purified recombinant proteins. Our results show that around half of the pathogenic exonic mutations alter RNA splicing or protein thermodynamic stability, both of which can lead to cMyBP-C haploinsufficiency. These molecular phenotypes are not found in control, non-pathogenic variants. Remarkably, the remaining pathogenic missense mutations appear to result in stable proteins, for which the cause of pathogenicity remains unknown. We propose that examination of protein haploinsufficiency drivers can define pathogenicity of genetic variants associated with HCM, decisive for the clinical management of patients and their families. |
| Databáze: | OpenAIRE |
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