title: 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.
abstract: 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.
  
  
  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(v beta2b)), CACNA2D1 (Ca(v alpha2delta1)), 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 < or = 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 alpha1- and beta2b-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(v beta2b)-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.
authors.affiliation: Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 13501, USA. ca@mmrl.edu
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
authors.forename: Guido D
authors.initials: GD
authors.lastname: Pollevick
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Cordeiro
authors.forename: Oscar
authors.initials: O
authors.lastname: Casis
authors.forename: Michael C
authors.initials: MC
authors.lastname: Sanguinetti
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Aizawa
authors.forename: Alejandra
authors.initials: A
authors.lastname: Guerchicoff
authors.forename: Ryan
authors.initials: R
authors.lastname: Pfeiffer
authors.forename: Antonio
authors.initials: A
authors.lastname: Oliva
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
authors.forename: Philip
authors.initials: P
authors.lastname: Gelber
authors.forename: Elias P
authors.initials: EP
authors.lastname: Bonaros
authors.forename: Elena
authors.initials: E
authors.lastname: Burashnikov
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Wu
authors.forename: John D
authors.initials: JD
authors.lastname: Sargent
authors.forename: Stefan
authors.initials: S
authors.lastname: Schickel
authors.forename: Ralf
authors.initials: R
authors.lastname: Oberheiden
authors.forename: Atul
authors.initials: A
authors.lastname: Bhatia
authors.forename: Li-Fern
authors.initials: LF
authors.lastname: Hsu
authors.forename: Michel
authors.initials: M
authors.lastname: Haïssaguerre
authors.forename: Rainer
authors.initials: R
authors.lastname: Schimpf
authors.forename: Martin
authors.initials: M
authors.lastname: Borggrefe
authors.forename: Christian
authors.initials: C
authors.lastname: Wolpert
mesh_terms: D000328:Adult; D000818:Animals; D016466:CHO Cells; D015220:Calcium Channels / Q000235:genetics / Q000502:physiology; D020746:Calcium Channels, L-Type / Q000235:genetics* / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D016757:Death, Sudden, Cardiac; D004562:Electrocardiography; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D018408:Patch-Clamp Techniques; D010641:Phenotype; D012042:Registries; D017180:Tachycardia, Ventricular / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D014693:Ventricular Fibrillation / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D044465:White People / Q000235:genetics
chemical_list: C079146:CACNA1C protein, human; C425903:CACNA2D1 protein, human; C107597:CACNB2 protein, human; D015220:Calcium Channels; D020746:Calcium Channels, L-Type