A Novel Recessive Mutation in SPEG Causes Early Onset Dilated Cardiomyopathy

Autoři: Aviva Levitas aff001;  Emad Muhammad aff002;  Yuan Zhang aff004;  Isaac Perea Gil aff004;  Ricardo Serrano aff005;  Nashielli Diaz aff004;  Maram Arafat aff002;  Alexandra A. Gavidia aff004;  Michael S. Kapiloff aff005;  Mark Mercola aff005;  Yoram Etzion aff006;  Ruti Parvari aff002;  Ioannis Karakikes aff004;  Ricardo Serrano aff006;  Michael S. Kapiloff aff007;  Mark Mercola aff006;  Yoram Etzion aff008
Působiště autorů: Department of Pediatric Cardiology, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel aff001;  The Shraga Segal Department of Microbiology, Immunology & Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel aff002;  The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel aff003;  Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California, United States of America aff004;  Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America aff005;  Regenerative Medicine & Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel aff006;  Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, CA, USA aff006;  Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel aff007;  Cardiovascular Institute and Departments of Ophthalmology and Medicine, Stanford University, Stanford, CA, USA aff007;  Regenerative Medicine & Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel aff008;  Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel aff009
Vyšlo v časopise: A Novel Recessive Mutation in SPEG Causes Early Onset Dilated Cardiomyopathy. PLoS Genet 16(9): e32767. doi:10.1371/journal.pgen.1009000
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009000


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.

Klíčová slova:

Bone and mineral metabolism – Cardiomyocytes – CRISPR – Gene expression – Homozygosity – Induced pluripotent stem cells – Pathogenesis – Sarcomeres – Human genomics


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