Accelerated inactivation of the L-type calcium current due to a mutation in CACNB2b underlies Brugada syndrome.
Recent studies have demonstrated an association between mutations in CACNA1c or CACNB2b and Brugada syndrome (BrS). Previously described mutations all caused a loss of function secondary to a reduction of peak calcium current (I(Ca)). We describe a novel CACNB2b mutation associated with BrS in which loss of function is caused by accelerated inactivation of I(Ca). The proband, a 32 year old male, displayed a Type I ST segment elevation in two right precordial ECG leads following a procainamide challenge. EP study was positive with induction of polymorphic VT/VF. Interrogation of implanted ICD revealed brief episodes of very rapid ventricular tachycardia. He was also diagnosed with vasovagal syncope. Genomic DNA was isolated from lymphocytes. All exons and intron borders of 15 ion channel genes were amplified and sequenced. The only mutation uncovered was a missense mutation (T11I) in CACNB2b. We expressed WT or T11I CACNB2b in TSA201 cells co-transfected with WT CACNA1c and CACNA2d. Patch clamp analysis showed no significant difference between WT and T11I in peak I(Ca) density, steady-state inactivation or recovery from inactivation. However, both fast and slow decays of I(Ca) were significantly faster in mutant channels between 0 and + 20 mV. Action potential voltage clamp experiments showed that total charge was reduced by almost half compared to WT. We report the first BrS mutation in CaCNB2b resulting in accelerated inactivation of L-type calcium channel current. Our results suggest that the faster current decay results in a loss-of-function responsible for the Brugada phenotype
Cordeiro
Jonathan M
JM
Department of Experimental Cardiology, Masonic Medical Research Laboratory, Utica, NY 13501, USA. jcordeiro@mmrl.edu
Marieb
Mark
M
Pfeiffer
Ryan
R
Calloe
Kirstine
K
Burashnikov
Elena
E
Antzelevitch
Charles
C
D000328:Adult; D000818:Animals; D001483:Base Sequence; D053840:Brugada Syndrome / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology*; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000235:genetics*; D004252:DNA Mutational Analysis; D004285:Dogs; D006801:Humans; D015640:Ion Channel Gating; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D018408:Patch-Clamp Techniques; D013997:Time Factors; D014463:Ultrasonography
C107597:CACNB2 protein, human; D020746:Calcium Channels, L-Type; D050505:Mutant Proteins