Mutations of the Cardiac Ryanodine Receptor (RyR2) Gene in Familial Polymorphic Ventricular Tachycardia

TLDR

Familial polymorphic ventricular tachycardia is an autosomal‑dominant disorder with early onset, a ~30 % mortality by age 30, and is characterized by exercise‑triggered bidirectional and polymorphic ventricular tachycardias without structural heart disease. The study demonstrates that patients with familial polymorphic ventricular tachycardia carry missense mutations in the cardiac sarcoplasmic reticulum calcium‑release channel RyR2. Three distinct missense mutations in RyR2 (P2328S, Q4201R, V4653F) were found to cosegregate with the arrhythmic phenotype in three large families, were absent in unaffected members and 100 controls, and together with identified SNPs suggest that RyR2 mutations underlie this inherited polymorphic tachycardia, establishing a new class of myocardial calcium‑signaling disorders.

Abstract

Background —Familial polymorphic ventricular tachycardia is an autosomal-dominant, inherited disease with a relatively early onset and a mortality rate of ≈30% by the age of 30 years. Phenotypically, it is characterized by salvoes of bidirectional and polymorphic ventricular tachycardias in response to vigorous exercise, with no structural evidence of myocardial disease. We previously mapped the causative gene to chromosome 1q42-q43. In the present study, we demonstrate that patients with familial polymorphic ventricular tachycardia have missense mutations in the cardiac sarcoplasmic 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 the nonaffected family members and in 100 healthy controls. In addition to identifying 3 causative mutations, we identified a number of single nucleotide 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 least one variety of inherited polymorphic tachycardia. These findings define a new entity of disorders of myocardial calcium signaling.