Desmoglein 2 mutant mice reproduce arrhythmogenic right ventricular cardiomyopathy patients' phenotype

Abstract Background Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is inherited cardiac disease with unresolved treatment. ARVC progressive and leads to lethal arrhythmias terminal heart failure. Most often encountered mutations are in desmosomal genes [1]. Purpose We aimed generate transgenic mice exact copy of genetic defects found Japanese cohort patients, describe the phenotype, identify target for curative therapy. Methods CRISPR/Cas9 genome editing was used knock-in two most common point patients: DSG2 292R>C 494D>A [2] (mouse equivalent positions 297R 499D, respectively). To analyze phenotype we imaging techniques - echography MRI as well telemetry, treadmill, immunohistochemistry, confocal microscopy, histology, Western blot. Results In vivo observations demonstrated inequalities phenotypical presentation between mutations. Some 297C (both hetero- homozygous) died suddenly, starting from age 9 weeks, contrast surviving all 499A carriers. Dissection suddenly reveals enlarged cavities, mainly right heart. addition, homozygous hearts present pale zones scattered over Paraffin sections this stained hematoxilin/eosin Masson's trichrome show myocardial areas absent myocytes, collagen accumulation calcifications. With exception mice, spontaneous development Dsg2 starts after 25th weeks age. Both mutant gradually developed dysfunction (echography MRI, Fig. 1) echographically visible left ventricular wall infiltrations. Heterozygous mutation produces more severe that develops earlier. Similar human ARVC, degree damage vary significantly. It known physical activity aggravates may cause sudden death. evaluate effect stress on subjected 11 old animals treadmill exercise. Training 8 provoked failure both significantly earlier than natural progress phenotype. No mouse suddenly. Telemetry experiment electrical instability showing conduction rhythm abnormalities (Fig. 2). Apoptosis detected by TUNEL staining microscopy. protein expression not affected Conclusion generated model reproduces defect disease. There significant similarities our patients' Funding Acknowledgement Type funding sources: Public grant(s) – National budget only. Main source(s): KAKENHI