A Novel Recessive Mutation in SPEG Causes Early Onset Dilated Cardiomyopathy

• DOI: 10.1371/journal.pgen.1009000
• Publication Date: 2020-09-14T17:38:30Z
• Authors: 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
• Keywords: Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is a common cause of heart failure and sudden cardiac death. It has been estimated that up to half DCM cases are hereditary. Mutations in more than 50 genes, primarily autosomal dominant, have reported. Although rare, recessive mutations thought contribute considerably DCM, especially young children. Here we identified novel mutation the striated muscle enriched protein kinase (SPEG, p. E1680K) gene family with nonsyndromic, early onset DCM. To ascertain pathogenicity this mutation, generated SPEG E1680K homozygous mutant human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) using CRISPR/Cas9-mediated genome editing. Functional studies iPSC-CMs showed aberrant calcium homeostasis, impaired contractility, sarcomeric disorganization, recapitulating hallmarks By combining genetic analysis iPSCs, editing, functional assays, as associated provide evidence for its vitro. Our study provides conceptual paradigm establishing genotype-phenotype associations inheritance.