An SCN1B Variant Affects Both Cardiac-Type (NaV1.5) and Brain-Type (NaV1.1) Sodium Currents and Contributes to Complex Concomitant Brain and Cardiac Disorders

Voltage-gated sodium (Na-V) channels are transmembrane proteins that initiate and propagate neuronal and cardiac action potentials. Na-V channel beta subunits have been widely studied due to their modulatory role. Mice null for Scn1b, which encodes Na-V beta 1 and beta 1b subunits, have defects in neuronal development and excitability, spontaneous generalized seizures, cardiac arrhythmias, and early mortality. A mutation in exon 3 of SCN1B, c.308A>T leading to beta 1_p.D103V and beta 1b_p.D103V, was previously found in a patient with a history of proarrhythmic conditions with progressive atrial standstill as well as cognitive and motor deficits accompanying structural brain abnormalities. We investigated whether beta 1 or beta 1b subunits carrying this mutation affect Na(V)1.5 and/or Na(V)1.1 currents using a whole cell patch-clamp technique in tsA201 cells. We observed a decrease in sodium current density in cells co-expressing Na(V)1.5 or Na(V)1.1 and beta 1(D103V) compared to beta 1(WT). Interestingly, beta 1b(D103V) did not affect Na(V)1.1 sodium current density but induced a positive shift in the voltage dependence of inactivation and a faster recovery from inactivation compared to beta 1b(WT). The beta 1b(D103V) isoform did not affect Na(V)1.5 current properties. Although the SCN1B_c.308A>T mutation may not be the sole cause of the patient's symptoms, we observed a clear loss of function in both cardiac and brain sodium channels. Our results suggest that the mutant beta 1 and beta 1b subunits play a fundamental role in the observed electrical dysfunction.