Key result
Dsp S311A mice recapitulate DSP-cardiomyopathies, driving early biventricular failure in homozygotes and arrhythmias in heterozygotes.
Why the study?
Pathogenic DSP variants cause arrhythmogenic cardiomyopathies with variable inheritance, but the genotype-dependent mechanisms underlying dominant versus recessive forms remained incompletely understood.
The Dsp S311A knock-in mouse model faithfully recapitulates dominant and recessive DSP-cardiomyopathies, providing a preclinical platform to study arrhythmogenic mechanisms.
Dsp S311A mice replicate DSP cardiomyopathy phenotypes; leaves open translation to human therapies or trials.
Background Pathogenic DSP variants cause arrhythmogenic cardiomyopathies (ACM) with variable inheritance. Recessive mutations lead to syndromic forms such as Carvajal syndrome, while dominant variants cause left-dominant DSP-cardiomyopathy (DSP-CM) characterized by early arrhythmias, inflammation, and fibrosis. Methods A knock-in mouse carrying the Dsp S311A mutation, orthologous to the human hotspot S299R, was generated. Heterozygous and homozygous mice underwent longitudinal echocardiographic, ECG telemetry, histological, ultrastructural, and molecular characterization under basal and exercise conditions. Results Homozygous Dsp S311A/S311A mice developed early biventricular failure, subepicardial necrosis, inflammation, replacement fibrosis, and spontaneous arrhythmias, reproducing Carvajal syndrome. Remarkably, heterozygous Dsp WT/S311A animals exhibited spontaneous ventricular arrhythmias and high susceptibility to exercise-induced sudden death before systolic dysfunction. These dominant traits were accompanied by biventricular patchy fibrosis, more prominent in the left ventricle, cardiomyocyte apoptosis, and inflammation. Both genotypes showed early desmosomal remodeling and Connexin-43 mislocalization, while β-catenin activation and DSP/DSG2 downregulation were confined to homozygotes. Conclusions The Dsp S311A model faithfully recapitulates dominant and recessive DSP-cardiomyopathies, linking desmosomal remodeling to early electrical instability. It provides a unique preclinical platform to unravel arrhythmogenic mechanisms and test targeted therapies.
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Guazzo et al. (2026) studied Arrhythmogenic cardiomyopathies (ACM). Dsp S311A mutation vs. Wild-type (implied) was evaluated on Phenotypic characterization (echocardiographic, ECG telemetry, histological, ultrastructural, and molecular). A Dsp S311A knock-in mouse model recapitulated dominant and recessive DSP-cardiomyopathies, with homozygous mice developing early biventricular failure and heterozygous mice exhibiting arrhythmias.
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