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

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          Abstract

          Familial polymorphic ventricular tachycardia is an autosomal-dominant, inherited disease with a relatively early onset and a mortality rate of approximately 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]). 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. 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.

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          Most cited references17

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          SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome.

          Long QT syndrome (LQT) is an inherited disorder that causes sudden death from cardiac arrhythmias, specifically torsade de pointes and ventricular fibrillation. We previously mapped three LQT loci: LQT1 on chromosome 11p15.5, LQT2 on 7q35-36, and LQT3 on 3p21-24. Here we report genetic linkage between LQT3 and polymorphisms within SCN5A, the cardiac sodium channel gene. Single strand conformation polymorphism and DNA sequence analyses reveal identical intragenic deletions of SCN5A in affected members of two unrelated LQT families. The deleted sequences reside in a region that is important for channel inactivation. These data suggest that mutations in SCN5A cause chromosome 3-linked LQT and indicate a likely cellular mechanism for this disorder.
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            Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia.

            Malignant hyperthermia (MH) causes neurological, liver, and kidney damage and death in humans and major economic losses in the swine industry. A single point mutation in the porcine gene for the skeletal muscle ryanodine receptor (ryr1) was found to be correlated with MH in five major breeds of lean, heavily muscled swine. Haplotyping suggests that the mutation in all five breeds has a common origin. Assuming that this is the causal mutation for MH, the development of a noninvasive diagnostic test will provide the basis for elimination of the MH gene or its controlled inclusion in swine breeding programs.
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              Cardiac conduction defects associate with mutations in SCN5A.

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                Author and article information

                Journal
                Circulation
                Circulation
                Ovid Technologies (Wolters Kluwer Health)
                0009-7322
                1524-4539
                January 30 2001
                January 30 2001
                : 103
                : 4
                : 485-490
                Affiliations
                [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.).
                Article
                10.1161/01.CIR.103.4.485
                11157710
                9f5df9a8-9486-419a-b2f6-a8120db6cda7
                © 2001
                History

                Molecular medicine,Neurosciences
                Molecular medicine, Neurosciences

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