Mutations in the cardiac L-type calcium channel associated with inherited J-wave syndromes and sudden cardiac death.
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.
Burashnikov
Elena
E
Masonic Medical Research Laboratory, Utica, New York 13501, USA.
Pfeiffer
Ryan
R
Barajas-Martinez
Héctor
H
Delpón
Eva
E
Hu
Dan
D
Desai
Mayurika
M
Borggrefe
Martin
M
Häissaguerre
Michel
M
Kanter
Ronald
R
Pollevick
Guido D
GD
Guerchicoff
Alejandra
A
Laiño
Ruben
R
Marieb
Mark
M
Nademanee
Koonlawee
K
Nam
Gi-Byoung
GB
Robles
Roberto
R
Schimpf
Rainer
R
Stapleton
Dwight D
DD
Viskin
Sami
S
Winters
Stephen
S
Wolpert
Christian
C
Zimmern
Samuel
S
Veltmann
Christian
C
Antzelevitch
Charles
C
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*
C079146:CACNA1C protein, human; C425903:CACNA2D1 protein, human; C107597:CACNB2 protein, human; D015220:Calcium Channels; D020746:Calcium Channels, L-Type
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