A Dsp S311A knock-in mouse reveals genotype-dependent mechanisms driving dominant and recessive DSP cardiomyopathies
A Guazzo, I P V Induja Perumal Vanaja, A D B Anna Di Bona, R B Riccardo Bariani, M C D Maria Claudia Disalvo, N K Nicolas Kuperwasser, P D Pierre David, M L M Maria Lopez-Moreno, B B Barbara Bauce, G M Giovanni Minervini, J M P P Jose Maria Perez Pomares, M P Mario Pende, C B Cristina Basso, M M Marco Mongillo, T Z Tania ZagliaAbstract
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.