Characterization of a novel mutation in the cardiac ryanodine receptor that results in catecholaminergic polymorphic ventricular tachycardia

Catecholaminergic polymorphic ventricular tachycardia (C pV T) is an arrhythmogenic disease that manifests as syncope or sudden death during high adrenergic tone in the absence of structural heart defects. It is primarily caused by mutations in the cardiac ryanodine receptor (RyR2). The mechanism by which these mutations cause arrhythmia remains controversial, with discrepant findings related to the role of the RyR2 binding protein FKB p1 2.6. The purpose of this study was to characterize a novel RyR2 mutation identified in a kindred with clinically diagnosed CpV T. si ngle-strand conformational polymorphism analysis and direct DNA sequencing were used to screen the RyR2 gene for mutations. si te-directed mutagenesis was employed to introduce the mutation into the mouse RyR2 cDNA. The impact of the mutation on the interaction between RyR2 and a 12.6 kDa FK506 binding protein (FKBp1 2.6) was deter- mined by immunoprecipitation and immunoblotting and its effect on RyR2 function was characterized by single cell Ca 2+