(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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 H. Swan, P. J. Laitinen, and L. Toivonen Volatile Anesthetics and Succinylcholine in Cardiac Ryanodine Receptor Defects Anesth. Analg., August 1, 2004; 99(2): 435 - 437. [Abstract] [Full Text] [PDF]
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 A. Bagattin, C. Veronese, B. Bauce, W. Wuyts, L. Settimo, A. Nava, A. Rampazzo, and G. A. Danieli Denaturing HPLC-Based Approach for Detecting RYR2 Mutations Involved in Malignant Arrhythmias Clin. Chem., July 1, 2004; 50(7): 1148 - 1155. [Abstract] [Full Text] [PDF]
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S. E. Lehnart, X. H.T. Wehrens, P. J. Laitinen, S. R. Reiken, S.-X. Deng, Z. Cheng, D. W. Landry, K. Kontula, H. Swan, and A. R. Marks Sudden Death in Familial Polymorphic Ventricular Tachycardia Associated With Calcium Release Channel (Ryanodine Receptor) Leak Circulation, June 29, 2004; 109(25): 3208 - 3214. [Abstract] [Full Text] [PDF]
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B. P. Delisle, B. D. Anson, S. Rajamani, and C. T. January Biology of Cardiac Arrhythmias: Ion Channel Protein Trafficking Circ. Res., June 11, 2004; 94(11): 1418 - 1428. [Abstract] [Full Text] [PDF]
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S. S. Chugh, O. Senashova, A. Watts, P. T. Tran, Z. Zhou, Q. Gong, J. L. Titus, and S. J. Hayflick Postmortem molecular screening in unexplained sudden death J. Am. Coll. Cardiol., May 5, 2004; 43(9): 1625 - 1629. [Abstract] [Full Text] [PDF]
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S. Viatchenko-Karpinski, D. Terentyev, I. Gyorke, R. Terentyeva, P. Volpe, S. G. Priori, C. Napolitano, A. Nori, S. C. Williams, and S. Gyorke Abnormal Calcium Signaling and Sudden Cardiac Death Associated With Mutation of Calsequestrin Circ. Res., March 5, 2004; 94(4): 471 - 477. [Abstract] [Full Text] [PDF]
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S. G. Priori Inherited Arrhythmogenic Diseases: The Complexity Beyond Monogenic Disorders Circ. Res., February 6, 2004; 94(2): 140 - 145. [Abstract] [Full Text] [PDF]
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P.D. Allen Not All Sudden Death Is the Same Circ. Res., September 19, 2003; 93(6): 484 - 486. [Full Text] [PDF]
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C. H. George, G. V. Higgs, and F. A. Lai Ryanodine Receptor Mutations Associated With Stress-Induced Ventricular Tachycardia Mediate Increased Calcium Release in Stimulated Cardiomyocytes Circ. Res., September 19, 2003; 93(6): 531 - 540. [Abstract] [Full Text] [PDF]
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N Sumitomo, K Harada, M Nagashima, T Yasuda, Y Nakamura, Y Aragaki, A Saito, K Kurosaki, K Jouo, M Koujiro, et al. Catecholaminergic polymorphic ventricular tachycardia: electrocardiographic characteristics and optimal therapeutic strategies to prevent sudden death Heart, January 1, 2003; 89(1): 66 - 70. [Abstract] [Full Text] [PDF]
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M. Scoote and A. J Williams The cardiac ryanodine receptor (calcium release channel): Emerging role in heart failure and arrhythmia pathogenesis Cardiovasc Res, December 1, 2002; 56(3): 359 - 372. [Abstract] [Full Text] [PDF]
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Z. Liu, J. Zhang, P. Li, S. R. W. Chen, and T. Wagenknecht Three-dimensional Reconstruction of the Recombinant Type 2 Ryanodine Receptor and Localization of Its Divergent Region 1 J. Biol. Chem., November 22, 2002; 277(48): 46712 - 46719. [Abstract] [Full Text] [PDF]
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A. V. Postma, I. Denjoy, T. M. Hoorntje, J.-M. Lupoglazoff, A. Da Costa, P. Sebillon, M. M.A.M. Mannens, A. A.M. Wilde, and P. Guicheney Absence of Calsequestrin 2 Causes Severe Forms of Catecholaminergic Polymorphic Ventricular Tachycardia Circ. Res., October 18, 2002; 91 (8): e21 - e26. [Abstract] [Full Text] [PDF]
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D. Fatkin and R. M. Graham Molecular Mechanisms of Inherited Cardiomyopathies Physiol Rev, October 1, 2002; 82(4): 945 - 980. [Abstract] [Full Text] [PDF]
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 I. A. Khan Exercise-Induced Bidirectional Ventricular Tachycardia with Alternating Right and Left Bundle Branch Block-Type Patterns: A Case Report Angiology, September 1, 2002; 53(5): 593 - 598. [Abstract] [PDF]
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P.D. Allen Leaky "Feet" and Sudden Death Circ. Res., August 9, 2002; 91(3): 181 - 182. [Full Text] [PDF]
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D. Jiang, B. Xiao, L. Zhang, and S.R. W. Chen Enhanced Basal Activity of a Cardiac Ca2+ Release Channel (Ryanodine Receptor) Mutant Associated With Ventricular Tachycardia and Sudden Death Circ. Res., August 9, 2002; 91(3): 218 - 225. [Abstract] [Full Text] [PDF]
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B. Bauce, A. Rampazzo, C. Basso, A. Bagattin, L. Daliento, N. Tiso, P. Turrini, G. Thiene, G. A. Danieli, and A. Nava Screening for ryanodine receptor type 2 mutations in families with effort-induced polymorphic ventricular arrhythmias and sudden death: Early diagnosis of asymptomatic carriers J. Am. Coll. Cardiol., July 17, 2002; 40(2): 341 - 349. [Abstract] [Full Text] [PDF]
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A. R. Marks Clinical Implications of Cardiac Ryanodine Receptor/Calcium Release Channel Mutations Linked to Sudden Cardiac Death Circulation, July 2, 2002; 106(1): 8 - 10. [Full Text] [PDF]
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S. G. Priori, C. Napolitano, M. Memmi, B. Colombi, F. Drago, M. Gasparini, L. DeSimone, F. Coltorti, R. Bloise, R. Keegan, et al. Clinical and Molecular Characterization of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia Circulation, July 2, 2002; 106(1): 69 - 74. [Abstract] [Full Text] [PDF]
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M.H. Gollob and R. Roberts AMP-activated protein kinase and familial Wolff-Parkinson-White syndrome: new perspectives on heart development and arrhythmogenesis Eur. Heart J., May 1, 2002; 23(9): 679 - 681. [Full Text] [PDF]
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A. R. Marks, S. Reiken, and S. O. Marx Progression of Heart Failure: Is Protein Kinase A Hyperphosphorylation of the Ryanodine Receptor a Contributing Factor? Circulation, January 22, 2002; 105(3): 272 - 275. [Full Text] [PDF]
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 M. ELDAR, E. PRAS, and H. LAHAT A Missense Mutation in a Highly Conserved Region of CASQ2 Is Associated with Autosomal Recessive Catecholamine-induced Polymorphic Ventricular Tachycardia in Bedouin Families from Israel Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 333 - 338. [Abstract] [PDF]
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X.H.T. WEHRENS and A.R. MARKS Myocardial Disease in Failing Hearts: Defective Excitation-Contraction Coupling Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 533 - 542. [Abstract] [PDF]
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C. Gemayel, A. Pelliccia, and P. D. Thompson Arrhythmogenic right ventricular cardiomyopathy J. Am. Coll. Cardiol., December 1, 2001; 38(7): 1773 - 1781. [Abstract] [Full Text] [PDF]
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