TY - JOUR
T1 - A novel recessive mutation in speg causes early onset dilated cardiomyopathy
AU - Levitas, Aviva
AU - Muhammad, Emad
AU - Zhang, Yuan
AU - Gil, Isaac Perea
AU - Serrano, Ricardo
AU - Diaz, Nashielli
AU - Arafat, Maram
AU - Gavidia, Alexandra A.
AU - Kapiloff, Michael S.
AU - Mercola, Mark
AU - Etzion, Yoram
AU - Parvari, Ruti
AU - Karakikes, Ioannis
N1 - Publisher Copyright: © 2020 Levitas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85092216758&partnerID=8YFLogxK
U2 - https://doi.org/10.1371/journal.pgen.1009000
DO - https://doi.org/10.1371/journal.pgen.1009000
M3 - Article
C2 - 32925938
SN - 1553-7390
VL - 16
JO - PLoS Genetics
JF - PLoS Genetics
IS - 9 September
M1 - e1009000
ER -