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
| Autor: | Guido D. Pollevick, Atul Bhatia, Charles Antzelevitch, Yuesheng Wu, Antonio Oliva, John D. Sargent, Bernd Wollnik, Christian Wolpert, Li Fern Hsu, Michel Haïssaguerre, Ralf Oberheiden, Rainer Schimpf, Stefan Schickel, Michael C. Sanguinetti, Yoshiyasu Aizawa, Philip Gelber, Elena Burashnikov, Elias P. Bonaros, Jonathan M. Cordeiro, Alejandra Guerchicoff, Ryan Pfeiffer, Martin Borggrefe, Oscar Casis |
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| Rok vydání: | 2007 |
| Předmět: |
Adult
Male medicine.medical_specialty Patch-Clamp Techniques Calcium Channels L-Type Genetic Linkage Timothy syndrome Mutation Missense sudden death CHO Cells QT interval Sudden death White People Article Sudden cardiac death Electrocardiography Cricetulus Physiology (medical) Internal medicine Cricetinae medicine Animals Humans Registries Brugada syndrome Family Health business.industry Cardiac arrhythmia Short QT syndrome Settore MED/43 - MEDICINA LEGALE medicine.disease Endocrinology Death Sudden Cardiac Phenotype Ventricular fibrillation Ventricular Fibrillation Cardiology Mutagenesis Site-Directed Tachycardia Ventricular calcium channel Female Calcium Channels Cardiology and Cardiovascular Medicine business brugada syndrome |
| Zdroj: | Circulation. 115(4) |
| ISSN: | 1524-4539 |
| Popis: | 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 vβ2b ), CACNA2D1 (Ca vα2δ1 ), and CACNA1C tagged with enhanced yellow fluorescent protein (Ca v 1.2). 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 α 1 - and β 2b -subunits of the L-type calcium channel. Confocal microscopy revealed a defect in trafficking of A39V Ca v 1.2 channels but normal trafficking of channels containing G490R Ca v 1.2 or S481L Ca vβ2b -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. |
| Databáze: | OpenAIRE |
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