Abstract 16521: Novel Mutations in the Sodium Channel 2 Subunit Gene (SCN2B) Associated with Brugada Syndrome and Atrial Fibrillation
INTRODUCTION: Cardiac sodium channel β subunit mutations have been associated with several inherited cardiac arrhythmia syndromes. To date, 11 Brugada syndrome (BrS)-susceptibility genes have been identified, including SCN1B- and SCN3B-encoded NaVβ1 and β3. In the present study, we report the association of SCN2B mutations with BrS.
METHODS: A total of 269 subjects diagnosed with BrS (125 sodium blocker challenge-positive) and negative for BrS1-11 (196 male/73female) were analyzed genetically using PCR-based direct sequencing. All known exons and intron borders of SCN2B were amplified and sequenced. Wild type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp techniques. GFP-fused SCN5A was co-transfected with SCN2B-WT or mutant for assessment of trafficking.
RESULTS: We identified and characterized 3 missense mutations in SCN2B associated with 4 cases of BrS and AF (1.5%). Proband 1, a 32-y/o male with an ajmaline-induced Type-1 ST segment elevation (STE) in V1 and V2, carried a R28Q heterozygous mutation in SCN2B. His mother, also diagnosed with BrS, was R28Q positive. Proband 2, a 42-y/o male with recurrent presyncope, and proband 3, a 48-y/o male with a family history of sudden death and stillbirth, were both ajmaline-positive, and both were Y69H-SCN2B mutation positive. Proband 4, a 41-year old male displaying a spontaneous Type-1 STE and a history of atrial fibrillation (AF), was positive for P210L-SCN2B. The 3 mutations were heterozygous and were absent in 759, 806 and 600 healthy controls. Co-expression of SCN2B-R28Q, Y69H, P210L with SCN5A-WT resulted in a 29.6%, 41.1% and 71.5% smaller of peak sodium channel current (INa,P) compared to SCN5A/WT+SCN2B/WT (n = 8-12 respectively). Confocal microscopy revealed that SCN2B-P210L caused a defect in trafficking of Nav1.5.
CONCLUSION: Our results identify SCN2B, which encodes the NaVβ2 subunit, as a Brugada syndrome-susceptibility gene. Mutations in SCN2B cause a loss of function in peak sodium channel current secondary to defects in gating or trafficking.
- © 2012 by American Heart Association, Inc.