A Novel Recessive Mutation in SPEG Causes Early Onset Dilated Cardiomyopathy

by Aviva Levitas, Emad Muhammad, Yuan Zhang, Isaac Perea Gil, Ricardo Serrano, Nashielli Diaz, Maram Arafat, Alexandra A. Gavidia, Michael S. Kapiloff, Mark Mercola, Yoram Etzion, Ruti Parvari, Ioannis Karakikes Dilated cardiomyopathy (DCM) is a common cause of heart failure and sudden cardiac death. It has been estimated that up to half of DCM cases are hereditary. Mutations in more than 50 genes, primarily autosomal dominant, have been reported. Although rare, recessive mutations are thought to contribu te considerably to DCM, especially in young children. Here we identified a novel recessive mutation in the striated muscle enriched protein kinase (SPEG,p. E1680K) gene in a family with nonsyndromic, early onset DCM. To ascertain the pathogenicity of this mutation, we generatedSPEG E1680K homozygous mutant human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) using CRISPR/Cas9-mediated genome editing. Functional studies in mutant iPSC-CMs showed aberrant calcium homeostasis, impaired contractility, and sarcomeric disorganization, recapitulating the hallmarks of DCM. By combining genetic analysis with human iPSCs, genome editing, and functional assays, we identifiedSPEG E1680K as a novel mutation associated with early onset DCM and provide evidence for its pathogenicityin vitro. Our study provides a conceptual paradigm for establishing genotype-phenotype associations in DCM with autosomal recessive inheritance.
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research