title: Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death.
abstract: BACKGROUND
  L-type calcium channel (LTCC) mutations have been associated with Brugada syndrome (BrS), short QT (SQT) syndrome, and Timothy syndrome (LQT8). Little is known about the extent to which LTCC mutations contribute to the J-wave syndromes associated with sudden cardiac death.
  
  
  OBJECTIVE
  The purpose of this study was to identify mutations in the α1, β2, and α2δ subunits of LTCC (Ca(v)1.2) among 205 probands diagnosed with BrS, idiopathic ventricular fibrillation (IVF), and early repolarization syndrome (ERS). CACNA1C, CACNB2b, and CACNA2D1 genes of 162 probands with BrS and BrS+SQT, 19 with IVF, and 24 with ERS were screened by direct sequencing.
  
  
  RESULTS
  Overall, 23 distinct mutations were identified. A total of 12.3%, 5.2%, and 16% of BrS/BrS+SQT, IVF, and ERS probands displayed mutations in α1, β2, and α2δ subunits of LTCC, respectively. When rare polymorphisms were included, the yield increased to 17.9%, 21%, and 29.1% for BrS/BrS+SQT, IVF, and ERS probands, respectively. Functional expression of two CACNA1C mutations associated with BrS and BrS+SQT led to loss of function in calcium channel current. BrS probands displaying a normal QTc had additional variations known to prolong the QT interval.
  
  
  CONCLUSIONS
  The study results indicate that mutations in the LTCCs are detected in a high percentage of probands with J-wave syndromes associated with inherited cardiac arrhythmias, suggesting that genetic screening of Ca(v) genes may be a valuable diagnostic tool in identifying individuals at risk. These results are the first to identify CACNA2D1 as a novel BrS susceptibility gene and CACNA1C, CACNB2, and CACNA2D1 as possible novel ERS susceptibility genes.
authors.affiliation: Masonic Medical Research Laboratory, Utica, New York 13501, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Burashnikov
authors.forename: Ryan
authors.initials: R
authors.lastname: Pfeiffer
authors.forename: Héctor
authors.initials: H
authors.lastname: Barajas-Martinez
authors.forename: Eva
authors.initials: E
authors.lastname: Delpón
authors.forename: Dan
authors.initials: D
authors.lastname: Hu
authors.forename: Mayurika
authors.initials: M
authors.lastname: Desai
authors.forename: Martin
authors.initials: M
authors.lastname: Borggrefe
authors.forename: Michel
authors.initials: M
authors.lastname: Häissaguerre
authors.forename: Ronald
authors.initials: R
authors.lastname: Kanter
authors.forename: Guido D
authors.initials: GD
authors.lastname: Pollevick
authors.forename: Alejandra
authors.initials: A
authors.lastname: Guerchicoff
authors.forename: Ruben
authors.initials: R
authors.lastname: Laiño
authors.forename: Mark
authors.initials: M
authors.lastname: Marieb
authors.forename: Koonlawee
authors.initials: K
authors.lastname: Nademanee
authors.forename: Gi-Byoung
authors.initials: GB
authors.lastname: Nam
authors.forename: Roberto
authors.initials: R
authors.lastname: Robles
authors.forename: Rainer
authors.initials: R
authors.lastname: Schimpf
authors.forename: Dwight D
authors.initials: DD
authors.lastname: Stapleton
authors.forename: Sami
authors.initials: S
authors.lastname: Viskin
authors.forename: Stephen
authors.initials: S
authors.lastname: Winters
authors.forename: Christian
authors.initials: C
authors.lastname: Wolpert
authors.forename: Samuel
authors.initials: S
authors.lastname: Zimmern
authors.forename: Christian
authors.initials: C
authors.lastname: Veltmann
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D000328:Adult; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D053840:Brugada Syndrome / Q000235:genetics*; D015220:Calcium Channels / Q000235:genetics*; D020746:Calcium Channels, L-Type / Q000235:genetics*; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac; D004562:Electrocardiography; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D013577:Syndrome; D014693:Ventricular Fibrillation / Q000235:genetics*
chemical_list: C079146:CACNA1C protein, human; C425903:CACNA2D1 protein, human; C107597:CACNB2 protein, human; D015220:Calcium Channels; D020746:Calcium Channels, L-Type
references.citation: Heart Rhythm. 2005 Apr;2(4):429-40
references.pmid: 15898165
references.citation: Clin Chem. 2001 Aug;47(8):1390-5
references.pmid: 11468227
references.citation: Circ Cardiovasc Genet. 2009 Jun;2(3):270-8
references.pmid: 20031595
references.citation: Circulation. 2002 Nov 5;106(19):2514-9
references.pmid: 12417552
references.citation: Circulation. 2007 Jan 30;115(4):442-9
references.pmid: 17224476
references.citation: Physiol Genomics. 2004 Apr 13;17(2):183-200
references.pmid: 14762176
references.citation: Circulation. 2005 Aug 30;112(9):1251-8
references.pmid: 16116052
references.citation: Cell. 2004 Oct 1;119(1):19-31
references.pmid: 15454078
references.citation: Curr Opin Neurobiol. 2009 Jun;19(3):237-44
references.pmid: 19559597
references.citation: Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8089-96; discussion 8086-8
references.pmid: 15863612
references.citation: Circ Cardiovasc Genet. 2010 Apr;3(2):199-206
references.pmid: 20181576
references.citation: Pacing Clin Electrophysiol. 2010 Mar;33(3):274-85
references.pmid: 20025708
references.citation: Europace. 2003 Jul;5(3):235-42
references.pmid: 12842634
references.citation: J Biol Chem. 2003 Feb 14;278(7):5021-8
references.pmid: 12473653
references.citation: Circ Res. 2009 Aug 14;105(4):383-92
references.pmid: 19608980
references.citation: BMC Med Genet. 2008 Sep 23;9:87
references.pmid: 18808722
references.citation: Heart Rhythm. 2010 Oct;7(10):1466-71
references.pmid: 20558321
references.citation: Circulation. 2009 Nov 3;120(18):1752-60
references.pmid: 19841300
references.citation: J Mol Cell Cardiol. 2009 May;46(5):695-703
references.pmid: 19358333
references.citation: Circulation. 2005 Feb 8;111(5):659-70
references.pmid: 15655131
references.citation: Genome Biol. 2003;4(11):R72
references.pmid: 14611658
references.citation: J Cardiovasc Electrophysiol. 2009 Jan;20(1):93-8
references.pmid: 19120683
references.citation: Hum Mutat. 1998;11(1):1-3
references.pmid: 9450896
references.citation: N Engl J Med. 2008 May 8;358(19):2078-9
references.pmid: 18463391
references.citation: Pharmacol Rev. 2005 Dec;57(4):411-25
references.pmid: 16382099
references.citation: Europace. 2002 Jan;4(1):3-18
references.pmid: 11858152
references.citation: Circ Res. 2009 Jun 19;104(12):1373-81
references.pmid: 19461046
references.citation: N Engl J Med. 2008 May 8;358(19):2016-23
references.pmid: 18463377
references.citation: Cardiovasc Res. 2003 Jul 1;59(1):27-36
references.pmid: 12829173
references.citation: Cardiovasc Res. 2008 Jan;77(1):98-106
references.pmid: 18006462
references.citation: Heart Rhythm. 2010 Apr;7(4):549-58
references.pmid: 20153265
references.citation: J Biol Chem. 2005 Apr 1;280(13):12474-85
references.pmid: 15671035
references.citation: Heart Rhythm. 2005 May;2(5):507-17
references.pmid: 15840476
references.citation: J Pharmacol Exp Ther. 2002 Mar;300(3):724-8
references.pmid: 11861774
references.citation: J Biol Chem. 2008 Jun 6;283(23):15577-88
references.pmid: 18411278
references.citation: Hum Mutat. 2009 Sep;30(9):1256-66
references.pmid: 19606473
references.citation: J Physiol. 2006 Oct 1;576(Pt 1):87-102
references.pmid: 16809371
references.citation: Heart Rhythm. 2010 Jan;7(1):33-46
references.pmid: 20129283
references.citation: J Cardiovasc Electrophysiol. 2001 Nov;12(11):1223-9
references.pmid: 11761407
references.citation: Heart Rhythm. 2007 Feb;4(2):170-4
references.pmid: 17275752
references.citation: Eur Heart J. 2008 Jul;29(13):1670-80
references.pmid: 18508782