A Novel Recessive Mutation in SPEG Causes Early Onset Dilated Cardiomyopathy

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Stem Cell Biology

Background:

• Dilated cardiomyopathy (DCM) is a major cause of heart failure and sudden cardiac death.
• Hereditary factors contribute to up to 50% of DCM cases, with both dominant and recessive mutations implicated.
• Recessive mutations are particularly significant in pediatric DCM.

Purpose of the Study:

• To identify novel genetic mutations causing nonsyndromic, early-onset DCM.
• To investigate the pathogenicity of a newly identified recessive mutation in the SPEG gene (p. E1680K).
• To establish a genotype-phenotype correlation for autosomal recessive DCM.

Main Methods:

• Genetic analysis of a family with early-onset DCM to identify mutations.
• Generation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with the SPEG E1680K mutation using CRISPR/Cas9.
• In vitro functional assays on mutant iPSC-CMs to assess cellular phenotypes.

Main Results:

• A novel recessive mutation, SPEG p. E1680K, was identified in a family with early-onset DCM.
• Mutant iPSC-CMs exhibited disrupted calcium handling, reduced contractility, and sarcomeric abnormalities.
• These functional deficits in iPSC-CMs recapitulated key features of DCM.

Conclusions:

• The SPEG p. E1680K mutation is a novel cause of autosomal recessive early-onset DCM.
• This study provides in vitro evidence for the pathogenicity of the SPEG p. E1680K mutation.
• The findings offer a new paradigm for linking genotypes to phenotypes in DCM with recessive inheritance patterns.