Mechanism for cardiomyopathy and cardiac arrhythmia associated with a novel human titin variant
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Date
2025-05
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The Ohio State University
Abstract
A 62-year-old male presented with ventricular arrhythmia, cardiomyopathy and family history of cardiomyopathy, ventricular arrhythmias, and sudden cardiac death (SCD). Whole exome sequencing of proband and affected and unaffected family members revealed a novel five- nucleotide insertion in exon 193 of the titin (TTN) gene introducing a premature stop codon. TTN is a sarcomeric protein spanning the length of the sarcomere acting as passive tensioner in contraction dynamics. Previous studies have identified TTN variants resulting in expression of truncated titin (TTNtv), dilated cardiomyopathy (DCM), heart failure (HF), contractile dysfunction, and/or increased risks of ventricular arrythmias [1], [2]. To investigate the pathogenicity of this variant, the same insertion was introduced in the analogous locus in the mouse TTN gene (TTHtv-KI). TTNtv-KI heterozygous crosses yielded no homozygous offspring, suggesting embryonic lethality. Adult (>2mo) TTNtv-KI heterozygous (TTN+/-) and wild type (WT) mice were evaluated at baseline (no interventions) and subjected to a transaortic constriction (TAC) procedure to observe the impact of the heterozygous mutation on the cardiac remodeling response to chronic pressure overload. Animals were for cardiac function in vivo using echocardiograph (ECHO) and surface electrocardiograms (ECG). In vitro isolated ventricular myocytes were immunostained for titin at the C-terminus and N-terminus. Our findings showed compelling evidence that a novel TTN truncating mutation leads to functional cardiac impairment, altered electrophysiological responses, and structural changes in myocytes, contributing to a growing body of literature on the role of TTN in cardiac disease and highlight the importance of early functional assessments in understanding the impact of TTN mutations on heart disease.
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Keywords
Titin, Dilated Cardiomyopathy, Arrhythmia, Hypertrophy