Homozygous MYZAP mutation in hiPSC-CMs caused cytoskeletal and sarcomeric disruption, altered mitochondrial respiration, and contractile dysfunction with frequent delayed afterdepolarizations.
Patient-specific hiPSC-CMs reveal that a homozygous MYZAP truncating mutation causes dilated cardiomyopathy through intercalated disc disruption, mitochondrial dysfunction, and arrhythmogenic electrophysiological changes.
Dilated cardiomyopathy (DCM) remains a leading cause of heart failure lacking effective treatments. Despite clinical advances, its pathogenic mechanisms are diverse and unclear. Recent attention has increasingly focused on the intercalated disc (ID), a specialized structure essential for mechanical and electrical coupling between cardiomyocytes and implicated in hereditary cardiomyopathies. MYZAP, an ID protein involved in SRF signalling, directly interacts with key ID components including DSP, TJP1 and CDH2, contributing to cardiomyocytes stress adaptation. A homozygous truncating MYZAP mutation (c.388 C > T; p.Arg130*) has been found in DCM patients with fluctuating elevated troponin I concentrations. This variant causes a premature stop codon, predicted to result in loss-of-function. We aimed to explore genotype-phenotype associations and mechanisms underlying homozygous MYZAP mutation-linked DCM using a human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) model. MYZAP loss was confirmed by immunocytochemistry and RT-qPCR. Ultrastructural analysis revealed cytoskeletal and sarcomeric disruption, glycogen accumulation, and abnormal mitochondrial morphology. Elevated TNNT2 and NPPB were confirmed by RT-qPCR and ELISA, alongside upregulated DSP expression, suggesting perturbed ID networks. Metabolic profiling indicated altered mitochondrial respiration, while electrophysiological recordings revealed contractile dysfunction with frequent delayed afterdepolarizations, reflecting heightened arrhythmogenic potential. Our findings illuminate MYZAP’s role in DCM and support future therapeutic development.
Zakzook et al. (Tue,) conducted a other in Dilated cardiomyopathy (n=3). Homozygous MYZAP mutation (c.388C>T; p.Arg130*) vs. Healthy control and heterozygous MYZAP mutation was evaluated on Cellular, molecular, metabolic, and electrophysiological characteristics. Homozygous MYZAP mutation in hiPSC-CMs caused cytoskeletal and sarcomeric disruption, altered mitochondrial respiration, and contractile dysfunction with frequent delayed afterdepolarizations.