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(Circulation. 2007;115:442-449.)
© 2007 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Loss-of-Function Mutations in the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST-Segment Elevation, Short QT Intervals, and Sudden Cardiac Death

Charles Antzelevitch, PhD; Guido D. Pollevick, PhD; Jonathan M. Cordeiro, PhD; Oscar Casis, PhD; Michael C. Sanguinetti, PhD; Yoshiyasu Aizawa, MD, PhD; Alejandra Guerchicoff, PhD; Ryan Pfeiffer, BS; Antonio Oliva, MD, PhD; Bernd Wollnik, MD; Philip Gelber, MD; Elias P. Bonaros, Jr, MD; Elena Burashnikov, MS; Yuesheng Wu, MD; John D. Sargent, PhD; Stefan Schickel, MD; Ralf Oberheiden, MD; Atul Bhatia, MD; Li-Fern Hsu, MD; Michel Haïssaguerre, MD; Rainer Schimpf, MD; Martin Borggrefe, MD; Christian Wolpert, MD

From the Masonic Medical Research Laboratory (C.A., G.D.P., J.M.C., H.A., A.G., R.P., A.O., E.B., Y.W.), Utica, NY; Nora Eccles Harrison Cardiovascular Research and Training Institute (O.C., M.C.S., J.D.S.), University of Utah, Salt Lake City, Utah; Center for Molecular Medicine Cologne (B.W.), Institute of Human Genetics, University of Cologne, Germany; Cardiovascular Consultants of Long Island (P.G., E.P.B.), New Hyde Park, NY; Department of Internal Medicine (S.S., R.O.), Academic Hospital Oberhausen, Oberhausen, Germany; University of Wisconsin Medical School (A.B.), Milwaukee, Wis; Hopital Cardiologique du Haut-Leveque (L.-F.H., M.H.), Bordeaux, France; and 1st Department of Medicine-Cardiology (R.S., M.B., C.W.), University Hospital Mannheim, Faculty of Clinical Medicine of the University of Heidelberg, Mannheim, Germany. Dr Oliva is currently at the Catholic University in Rome, Italy.

Correspondence to Dr Charles Antzelevitch, Gordon K. Moe Scholar, Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 13501. E-mail ca{at}mmrl.edu

Received October 4, 2006; accepted November 22, 2006.

Background— Cardiac ion channelopathies are responsible for an ever-increasing number and diversity of familial cardiac arrhythmia syndromes. We describe a new clinical entity that consists of an ST-segment elevation in the right precordial ECG leads, a shorter-than-normal QT interval, and a history of sudden cardiac death.

Methods and Results— Eighty-two consecutive probands with Brugada syndrome were screened for ion channel gene mutations with direct sequencing. Site-directed mutagenesis was performed, and CHO-K1 cells were cotransfected with cDNAs encoding wild-type or mutant CACNB2b (Ca_vß2b), CACNA2D1 (Ca_v21), and CACNA1C tagged with enhanced yellow fluorescent protein (Ca_v1.2). Whole-cell patch-clamp studies were performed after 48 to 72 hours. Three probands displaying ST-segment elevation and corrected QT intervals 360 ms had mutations in genes encoding the cardiac L-type calcium channel. Corrected QT ranged from 330 to 370 ms among probands and clinically affected family members. Rate adaptation of QT interval was reduced. Quinidine normalized the QT interval and prevented stimulation-induced ventricular tachycardia. Genetic and heterologous expression studies revealed loss-of-function missense mutations in CACNA1C (A39V and G490R) and CACNB2 (S481L) encoding the ₁- and ß_2b-subunits of the L-type calcium channel. Confocal microscopy revealed a defect in trafficking of A39V Ca_v1.2 channels but normal trafficking of channels containing G490R Ca_v1.2 or S481L Ca_vß2b-subunits.

Conclusions— This is the first report of loss-of-function mutations in genes encoding the cardiac L-type calcium channel to be associated with a familial sudden cardiac death syndrome in which a Brugada syndrome phenotype is combined with shorter-than-normal QT intervals.

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