Abstract 1048: Loss of Function in Calcium Channel Activity Secondary to a Mutation in CACNB2b Modulates the Clinical Manifestation of a Combined Brugada Syndrome-Short QT Phenotype
Background: Cardiac ion channelopathies are responsible for a diversity of familial cardiac arrhythmias including the long QT (LQTS), short QT (SQTS) and Brugada (BrS) syndromes. Phenotypic overlap between LQTS and BrS is well known. We describe a case of overlap between BrS and a shorter than normal QT (SQT) and identify a genetic mutation responsible for modulation of this unique phenotype in a Caucasian family.
Methods: Genomic DNA was prepared from peripheral blood lymphocytes. All known exons of 13 candidate genes were amplified using intronic primers and sequenced. Site-directed mutagenesis was performed and CHO-K1 cells were co-transfected using a 1:1:1 molar ratio of WT or mutant CACNB2b (Cavβ2b), CACNA2D1 (Cavα2δ1) and CACNA1C tagged with enhanced yellow fluorescent protein (Cav1.2). Whole-cell patch clamp studies were performed after 48–72 hours of incubation.
Results: The proband, a 25 y/o male, presented with aborted SCD. QTc was 358 ms and a coved-type ST segment elevation was observed in V1 and V2 following an ajmaline challenge. Genetic analysis revealed no mutations in SCN5A or KCNH2, KCNQ1 and KCNJ2, genes previously linked to BrS and SQTS, respectively. Because ST segment elevation and QT abbreviation could be due to a gain of function in other K+ channels or to loss of function of Ca2+ ion channels, we screened for variations in, KCNE1, KCNE2, KCNE3, KCNE5, KCND3, KCNJ11, CACNA1C, CACNB2b, CACNA2D1. A mutation was only identified in CACNB2b, characterized by a C1442T transition in exon 13; predicting a substitution of Serine for Leucine at codon 481 (S481L), which was not present in 400 ethnically matched control alleles. The S481L mutation was identified in 5 of 6 affected family members from a total of 11 screened and absent in 4 of 5 unaffected family members. Co-expression of CACNA1C together with WT or mutant CACNB2b in the mammalian cell line indicated a 73% reduction in L-type calcium channel current at +10mV (WT=429.0±103.8, n=10; S481L=115.1±65.5 pA, n=5), with no shift in voltage dependence of the current.
Conclusion: We describe a new clinical entity, characterized by ST segment elevation in V1-V3 with a shorter than normal QT interval, whose clinical manifestation is modulated by a mutation in the β subunit of the cardiac calcium channel.