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

Author:

Laitinen Päivi J.1,Brown Kevin M.1,Piippo Kirsi1,Swan Heikki1,Devaney Joe M.1,Brahmbhatt Bhoomi1,Donarum Elizabeth A.1,Marino Michael1,Tiso Natascia1,Viitasalo Matti1,Toivonen Lauri1,Stephan Dietrich A.1,Kontula Kimmo1

Affiliation:

1. From the Department of Medicine, University of Helsinki, Helsinki, Finland (P.J.L., K.P., H.S., M.V., L.T., K.K.); the Research Center for Genetic Medicine, Children’s National Medical Center, Washington, DC (K.M.B., B.B., E.A.D., D.A.S.); the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD (K.M.B., D.A.S.); Transgenomic, Inc, Gaithersburg, MD (J.M.D., M.M.); and the Department of Biology, University of Padova, Padova, Italy (N.T.).

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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