DspS311A knock-in mice replicate the clinical-pathological features of dominant and recessive forms of Desmoplakin-related cardiomyopathies

Background/PurposeDesmoplakin (DSP) mutations are linked to familial cardiomyopathies with a very high arrhythmogenic propensity. While autosomal recessive inheritance forms manifest in the cardio-cutaneous Carvajal syndrome, the dominant-inheritance variants associate to DSP-cardiomyopathy (DSP-CM). This latter is a subtype of Arrhythmogenic Cardiomyopathy characterized by frequent myocarditis-like episodes, dominant left ventricular (LV) remodeling, recurrent premature ventricular contractions and life-threatening arrhythmias, frequently preceding LV dysfunction and dilation. Notably, DSP-CM evades the diagnostic identifiers of Arrhythmogenic Cardiomyopathy, further complicating risk-stratification and prediction. At the time being, the pathogenetic mechanisms underlying DSP-related cardiomyopathies are largely obscure and their elucidation is urgently required. MethodsTo this end, we employed CRISPR-Cas9 to generate a novel knock-in mouse model harboring a point mutation at the murine ortholog of human Serine-299, a mutation site previously identified in a family affected by left dominant-Arrhythmogenic Cardiomyopathy. In both heterozygotes and homozygotes, cardiac function was assessed by echocardiography and telemetry-ECG, at different ages. Results were correlated with heart structure, which was assessed by ultrastructural, histopathological and molecular/biochemical assays. The effects of moderate exercise on disease manifestations were tested. ResultsThe homo- and hetero-zygous expression of mutant DspS311A allele replicated the human cardiac phenotypes of Carvajal syndrome and DSP-CM, respectively. Indeed, DspS311A/S311A mice featured precocious dilated cardiomyopathy with biventricular fibrotic remodeling, aneurisms, systolic dysfunction, increased arrhythmic vulnerability, sudden death and, remarkably, cutaneous defects. Differently, DspWT/S311A mice did not show evident cutaneous alterations, and myocardial remodeling and contractile dysfunction developed later and were associated to increased cell death, inflammatory response and patchy fibrosis predominantly in the LV. Notably, as observed in certain patient subgroups, DspWT/S311A mice had electrophysiological alterations (i.e. QRS prolongation, distal conduction defects and sustained ventricular arrhythmias) prior to developing contractile dysfunction. Furthermore, in both genotypes, exercise accelerated myocardial remodeling and increased the incidence of arrhythmic mortality. ConclusionsOur novel DspS311A mice recapitulate the clinical and pathological features of the respective dominant (i.e. DSP-CM) and recessive (i.e. Carvajal syndrome) forms of DSP-related cardiomyopathies. Thus, DspS311A mice are a novel experimental model of human diseases, suited to test therapeutic interventions aimed at reducing the burden of stress-dependent SD.