(Circulation. 2001;103:485.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Mutations of the Cardiac Ryanodine Receptor (RyR2) Gene in Familial Polymorphic Ventricular Tachycardia
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.).
Correspondence to Kimmo Kontula, MD, PhD, Department of Medicine, University of Helsinki, 00290 Helsinki, Finland. E-mail: kimmo.kontula{at}hus.fi or to Dietrich A. Stephan, PhD, Research Center for Genetic Medicine, Children’s National Medical Center, 111 Michigan Avenue, NW, Washington, DC 20010.
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.
Key Words: ryanodine receptor calcium release channel • sarcoplastic reticulum • tachycardia • genetics
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