Key result
The homozygous SPEG E1680K mutation causes early-onset dilated cardiomyopathy, characterized in vitro by aberrant calcium homeostasis, impaired contractility, and sarcomeric disorganization.
Why the study?
Recessive mutations are thought to contribute considerably to DCM, particularly in young children, but specific causal variants require identification and functional validation.
Does the SPEG E1680K mutation cause early-onset dilated cardiomyopathy and impair cardiomyocyte function in vitro?
Does the SPEG E1680K mutation cause early-onset dilated cardiomyopathy and impair cardiomyocyte function in vitro?
Warrants SPEG testing in early-onset familial DCM; leaves open prevalence and therapies in broader cohorts.
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 contribute 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 generated SPEG 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 identified SPEG E1680K as a novel mutation associated with early onset DCM and provide evidence for its pathogenicity in vitro. Our study provides a conceptual paradigm for establishing genotype-phenotype associations in DCM with autosomal recessive inheritance.
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Levitas et al. (2020) studied Early Onset Dilated Cardiomyopathy (n=5). SPEG E1680K mutation vs. Wild-type SPEG (in vitro) / healthy family members was evaluated on Pathogenicity of SPEG E1680K mutation (in vitro functional assays: calcium homeostasis, contractility, sarcomeric organization). The homozygous SPEG E1680K mutation causes early-onset dilated cardiomyopathy, characterized in vitro by aberrant calcium homeostasis, impaired contractility, and sarcomeric disorganization.
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