Abstract 362: Mutations in an Alternately Processed Sodium Channel Beta-1 Subunit Associated with Brugada Syndrome and Cardiac Conduction Defect.
Background: Loss of function mutations in SCN5A, encoding the cardiac sodium channel βsubunit, can cause Brugada syndrome (BrS) and progressive cardiac conduction disease. However, SCN5A mutations are not detected in a majority of patients with these syndromes, indicating the existence of other disease genes.
Methods and results: We screened the voltage-gated sodium-channel β1 subunit, encoded by SCN1B, in a large cohort of patients with BrS or cardiac conduction disease, and found no non-synonymous variants in the reported coding region. However, recent studies in rat and human have identified an alternate transcript of SCN1B that retains a portion of intron 3, and screening of this genomic fragment identified two different nucleotide variants, one in a patient with BrS and one in a patient with mild conduction disease. Both variants were predicted to generate a premature stop codon at the same amino acid (W179X) in the retained region and thereby eliminate the transmembrane spanning segment of the alternately processed subunit, β1b. The variants were absent in >1000 ethnically-matched control subjects. Real-time PCR identified β1b expression in heart, 5 times greater in Purkinje fiber (P<0.001) and 1.7 times greater in right ventricle (P=0.01) than left ventricular free wall. To assess function in vitro, CHO cells were transfected with SCN5A without β subunit, SCN5A with wild-type (WT) β1b subunit, or SCN5A with mutant β1b. WT β1b increased peak sodium current amplitude by 77% (P<0.001), and induced a negative shift in steady-state activation (−5.3 mV, P<0.001) and inactivation (−9.6 mV, P<0.001), compared to SCN5A alone. By contrast, sodium currents were unaltered by coexpression with W179X β1b.
Conclusions: An alternately processed sodium channel β1 subunit is expressed in heart and modulates cardiac sodium channel function. Loss of function mutations in the coding region of this subunit were identified in patients with BrS and conduction system disease. These data implicate SCN1B as a disease gene for loss of sodium channel function phenotypes.