Arrhythmogenic right ventricular cardiomyopathy in Boxer dogs is associated with calstabin2 deficiency.

OBJECTIVE:To examine the presence and effect of calstabin2-deficiency in Boxer dogs with arrhythmogenic right ventricular cardiomyopathy (ARVC). ANIMALS:Thirteen Boxer dogs with ARVC. MATERIALS AND METHODS:Tissue samples were collected for histopathology, oligonucleotide microarray, PCR, immunoelectrophoresis, ryanodine channel immunoprecipitation and single-channel recordings, and calstabin2 DNA sequencing. RESULTS:In cardiomyopathic Boxer dogs, myocardial calstabin2 mRNA and protein were significantly decreased as compared to healthy control dogs (calstabin2 protein normalized to tetrameric cardiac ryanodine receptor (RyR2) complex: affected, 0.51+/-0.04; control, 3.81+/-0.22; P<0.0001). Calstabin2 deficiency in diseased dog hearts was associated with a significantly increased open probability of single RyR2 channels indicating intracellular Ca(2+) leak. PCR-based sequencing of the promoter, exonic and splice site regions of the canine calstabin2 gene did not identify any causative mutations. CONCLUSIONS:Calstabin2 deficiency is a potential mechanism of Ca(2+) leak-induced ventricular arrhythmias and heart disease in Boxer dogs with ARVC.

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