Anti-CACNB2 monoclonal antibody, clone T9c-2 [FITC]

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-v beta 2b), CACNA2D1 ( Cav(alpha 2 delta 1)), 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 alpha(1)- and beta(2b)- subunits of the L-type calcium channel. Confocal microscopy revealed a defect in trafficking of A39V Cav1.2 channels but normal trafficking of channels containing G490R Ca(v)1.2 or S481L Ca-v beta 2b-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.

BackgroundCalcium voltage-gated channel auxiliary subunit 2 is a protein that, in humans, is encoded by the CACNB2 gene. The 2 subunit is an auxiliary protein of voltage-gated calcium channels, which is predominantly expressed in hippocampal pyramidal neurons. A single-nucleotide polymorphism at the CACNB2 gene (rs11013860) has been reported in genome-wide association studies to be associated with bipolar disorder (BD). However, the neural effects of rs11013860 expression are unknown. Thus, the current study investigated the mechanisms of how the CACNB2 gene influences hippocampal-cortical limbic circuits in patients with bipolar disorder (BD).MethodsA total of 202 subjects were studied [69 BD patients and 133 healthy controls (HC)]. Participants agreed to undergo resting-state functional magnetic resonance imaging (rs-fMRI) and have blood drawn for genetic testing. Participants were found to belong to either a CC group homozygous for the C-allele (17 BD, 41 HC), or an A-carrier group carrying the high risk A-allele (AA/CA genotypes; 52 BD, 92 HC). Brain activity was assessed using resting-state functional connectivity (rs-FC) analyses.ResultsA main effect of genotype showed that the rs-FC of the AA/CA group was elevated more than that of the CC-group between the hippocampus and the regions of right-inferior temporal, fusiform, and left-inferior occipital gyri. Additionally, a significant diagnosis x genotype interaction was noted between the hippocampus and right pars triangularis. Furthermore, in BD patients, the AA/CA group showed lower rs-FC when compared to that of the CC group. Additionally, individuals from HC within the AA/CA group showed higher rs-FC than that of the CC group. Finally, within C-allele-carrying groups, individuals with BD showed significantly increased rs-FC compared to that of HC.ConclusionsOur study demonstrates that BD patients with the CACNB2 rs11013860 AA/CA genotype may exhibit altered hippocampal-cortical connectivity.