A Novel Recessive Mutation in SPEG Causes Early Onset Dilated Cardiomyopathy

Abstract

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.

HPLC‐QTOF/MS‐based metabolomics to explore the molecular mechanisms of Yiqi Fumai Lyophilized Injection in heart failure mice

“…Cysteine sulfinic acid decarboxylase (CASD) is an important biosynthetic enzyme for taurine. The low activity of CASD is more likely to cause taurine deficiency which eventually leads to heart failure accompanied by myocardial fibrosis [41, 42]. Histamine, the product from histidine metabolism, is synthesized via catalytic decarboxylation of histidine by histidine decarboxylase (HDC) [43].…”

CRISPR-Cas Tools and Their Application in Genetic Engineering of Human Stem Cells and Organoids

“…CRISPR has also been applied to interrogate cardiac diseases, such as dilated cardiomyopathy (Briganti et al, 2020;Levitas et al, 2020;Rebs et al, 2020). Creation of gene reporters has helped characterize cardiac lineage subpopulations through dual tagging of TBX2 and NKX2-5 (Zhang et al, 2019), while tagging of a series of sarcomere-related genes aided their visualization at the sarcomere in real time (Roberts et al, 2019).…”

Striated Preferentially Expressed Protein Kinase (SPEG) in Muscle Development, Function, and Disease

“…Underlying these clinical phenotypes, cellular and molecular hallmarks of CNM include increased central nucleation of myofibers and variation in myofibers size, and disruptions in triadic structure and E-C coupling [ 10 , 44 , 45 ]. To date, 20 patients have been identified with SPEG mutations [ 23 , 44 , 46 , 47 , 48 , 49 ]. Figure 1 shows the location and mutation type of all reported SPEG variants.…”

“…Five additional patients from a single family showing isolated DCM without myopathy was recently described by Levitas et al [ 47 ] carrying homozygous missense mutation (c.5038G>A, p.Glu1680Lys) in the serine/threonine protein kinase (SK)-1 domain of SPEG. Functional studies in induced pluripotent stem cell-derived cardiomyocytes showed aberrant calcium homeostasis, impaired contractility, and sarcomeric disorganization [ 47 ]. We recently identified three patients with a homozygous in-frame deletion (c.9028_9030delGAG, p.Glu3010del) in the SK-2 domain of SPEG [ 49 ].…”