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(Circulation. 2001;103:196.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Mutations in the Cardiac Ryanodine Receptor Gene (hRyR2) Underlie Catecholaminergic Polymorphic Ventricular Tachycardia

Silvia G. Priori, MD, PhD; Carlo Napolitano, MD, PhD; Natascia Tiso, PhD; Mirella Memmi, PhD; Gabriele Vignati, MD; Raffaella Bloise, MD; Vincenzo Sorrentino, MD; Gian Antonio Danieli, BSc

From the Molecular Cardiology Laboratories, IRCCS Fondazione Salvatore Maugeri, Pavia, Italy (S.G.P., C.N., M.M., R.B.); Department of Cardiology, University of Pavia, Pavia, Italy (S.G.P.); Laboratory of Human Genetics, Department of Biology, University of Padova, Padova, Italy (N.T., G.A.D.); Cardiology Department A De Gasperis, Niguarda Hospital, Milan, Italy (G.V.); DIBIT, Scientific Institute San Raffaele, Milan, Italy (V.S.); and the Molecular Medicine Section, Department of Neuroscience, University of Siena, Italy (V.S).

Correspondence to Silvia G. Priori, MD, PhD, Director of Molecular Cardiology, Fondazione Salvatore Maugeri, Associate Professor of Cardiology, University of Pavia, Via Ferrata 8, 27100 Pavia, Italy. E-mail spriori{at}fsm.it

Background—Catecholaminergic polymorphic ventricular tachycardia is a genetic arrhythmogenic disorder characterized by stress-induced, bidirectional ventricular tachycardia that may degenerate into cardiac arrest and cause sudden death. The electrocardiographic pattern of this ventricular tachycardia closely resembles the arrhythmias associated with calcium overload and the delayed afterdepolarizations observed during digitalis toxicity. We speculated that a genetically determined abnormality of intracellular calcium handling might be the substrate of the disease; therefore, we considered the human cardiac ryanodine receptor gene (hRyR2) a likely candidate for this genetically transmitted arrhythmic disorder.

Methods and Results—Twelve patients presenting with typical catecholaminergic polymorphic ventricular tachycardia in the absence of structural heart abnormalities were identified. DNA was extracted from peripheral blood lymphocytes, and single-strand conformation polymorphism analysis was performed on polymerase chain reaction–amplified exons of the hRyR2 gene. Four single nucleotide substitutions leading to missense mutations were identified in 4 probands affected by the disease. Genetic analysis of the asymptomatic parents revealed that 3 probands carried de novo mutations. In 1 case, the identical twin of the proband died suddenly after having suffered syncopal episodes. The fourth mutation was identified in the proband, in 4 clinically affected family members, and in none of 3 nonaffected family members in a kindred with 2 sudden deaths that occurred at 16 and 14 years, respectively, in the sisters of the proband.

Conclusions—We demonstrated that, in agreement with our hypothesis, hRyR2 is a gene responsible for catecholaminergic polymorphic ventricular tachycardia.

Key Words: arrhythmia • genetics • tachycardia • ryanodine receptor calcium release channel

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				M. Cerrone, B. Colombi, M. Santoro, M. R. di Barletta, M. Scelsi, L. Villani, C. Napolitano, and S. G Priori Bidirectional Ventricular Tachycardia and Fibrillation Elicited in a Knock-In Mouse Model Carrier of a Mutation in the Cardiac Ryanodine Receptor Circ. Res., May 27, 2005; 96(10): e77 - e82. [Abstract] [Full Text] [PDF]

				D. J. Tester, L. J. Kopplin, W. Creighton, A. P. Burke, and M. J. Ackerman Pathogenesis of Unexplained Drowning: New Insights From a Molecular Autopsy Mayo Clin. Proc., May 1, 2005; 80(5): 596 - 600. [Abstract] [PDF]

				T. T. Beery The Genetics of Cardiac Arrhythmias Biol Res Nurs, April 1, 2005; 6(4): 249 - 261. [Abstract] [PDF]

				D. Terentyev, S. E. Cala, T. D. Houle, S. Viatchenko-Karpinski, I. Gyorke, R. Terentyeva, S. C. Williams, and S. Gyorke Triadin Overexpression Stimulates Excitation-Contraction Coupling and Increases Predisposition to Cellular Arrhythmia in Cardiac Myocytes Circ. Res., April 1, 2005; 96(6): 651 - 658. [Abstract] [Full Text] [PDF]

				R. P. Katra and K. R. Laurita Cellular Mechanism of Calcium-Mediated Triggered Activity in the Heart Circ. Res., March 18, 2005; 96(5): 535 - 542. [Abstract] [Full Text] [PDF]

				K. A. Hodgkinson, P. S. Parfrey, A. S. Bassett, C. Kupprion, J. Drenckhahn, M. W. Norman, L. Thierfelder, S. N. Stuckless, E. L. Dicks, W. J. McKenna, et al. The impact of implantable cardioverter-defibrillator therapy on survival in autosomal-dominant arrhythmogenic right ventricular cardiomyopathy (ARVD5) J. Am. Coll. Cardiol., February 1, 2005; 45(3): 400 - 408. [Abstract] [Full Text] [PDF]

				C. Antzelevitch Cardiac repolarization. The long and short of it Europace, January 1, 2005; 7(s2): S3 - S9. [Abstract] [Full Text] [PDF]

				Z. Kubalova, I. Gyorke, R. Terentyeva, S. Viatchenko-Karpinski, D. Terentyev, S. C Williams, and S. Gyorke Modulation of cytosolic and intra-sarcoplasmic reticulum calcium waves by calsequestrin in rat cardiac myocytes J. Physiol., December 1, 2004; 561(2): 515 - 524. [Abstract] [Full Text] [PDF]

				X. H. T. Wehrens and A. R. Marks Sudden Unexplained Death Caused by Cardiac Ryanodine Receptor (RyR2) Mutations Mayo Clin. Proc., November 1, 2004; 79(11): 1367 - 1371. [PDF]

				D. J. Tester, D. B. Spoon, H. H. Valdivia, J. C. Makielski, and M. J. Ackerman Targeted Mutational Analysis of the RyR2-Encoded Cardiac Ryanodine Receptor in Sudden Unexplained Death: A Molecular Autopsy of 49 Medical Examiner/Coroner's Cases Mayo Clin. Proc., November 1, 2004; 79(11): 1380 - 1384. [Abstract] [PDF]