Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia

Background-Familial polymorphic ventricular tachycardia is an autosomal-dom inant, inherited disease with a relatively early onset and a mortality rate of approximate to 30% by the age of 30 years. Phenotypically, it is charac terized by salvoes of bidirectional and polymorphic ventricular tachycardia s in response to vigorous exercise, with no structural evidence of myocardi al disease. We previously mapped the causative gene to chromosome 1q42-q43. In the present study, we demonstrate that patients with familial polymorph ic ventricular tachycardia have missense mutations in the cardiac sarcoplas mic reticulum calcium release channel (ryanodine receptor type 2 [RyR2]). Methods and Results-In 3 large families studied, 3 different RyR2 mutations (P2328S, Q4201R, V4653F) were detected and shown to fully cosegregate with the characteristic arrhythmic phenotype. These mutations were absent in th e nonaffected family members and in 100 healthy controls. In addition to id entifying 3 causative mutations, we identified a number of single nucleotid e polymorphisms that span the genomic structure of RyR2 and will be useful for candidate-based association studies for other arrhythmic disorders. Conclusions-Our data illustrate that mutations of the RyR2 gene cause at le ast one variety of inherited polymorphic tachycardia. These findings define a new entity of disorders of myocardial calcium signaling.