Journal Article

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

Srinivasan, Chandra, Scornik, Fabiana S., Riuró, Helena, Parnes, Mered, Martinez-Moreno, Rebecca, Selga, Elisabet, Pérez, Guillermo J., Brugada, Ramon, Carreras, David, Wangler, Michael F.

2020

Overview

Voltage-gated sodium (Na ) channels are transmembrane proteins that initiate and propagate neuronal and cardiac action potentials. Na channel β subunits have been widely studied due to their modulatory role. Mice null for , which encodes Na β1 and β1b subunits, have defects in neuronal development and excitability, spontaneous generalized seizures, cardiac arrhythmias, and early mortality. A mutation in exon 3 of , c.308A>T leading to β1_p.D103V and β1b_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 β1 or β1b subunits carrying this mutation affect Na 1.5 and/or Na 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 1.5 or Na 1.1 and β1 compared to β1 . Interestingly, β1b did not affect Na 1.1 sodium current density but induced a positive shift in the voltage dependence of inactivation and a faster recovery from inactivation compared to β1b . The β1b isoform did not affect Na 1.5 current properties. Although the _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 β1 and β1b subunits play a fundamental role in the observed electrical dysfunction.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Arrhythmia / brain hyperexcitability / Cardiac arrhythmia / Cell and Developmental Biology / Channel gating / Convulsions & seizures / Excitability / Heart / Long QT syndrome / Mutagenesis / Mutation / NaV1.1 / NaV1.5 / NaVβ1 / NaVβ1b / Proteins / Seizures / Sodium / Sodium channels (voltage-gated)