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

Abstract

Voltage-gated sodium (Na V ) channels are transmembrane proteins that initiate and propagate neuronal and cardiac action potentials. Na V channel β subunits have been widely studied due to their modulatory role. Mice null for Scn1b , which encodes Na V 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 SCN1B , 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 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 β1 D103V compared to β1 WT . Interestingly, β1b 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 β1b WT . The β1b 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 β1 and β1b subunits play a fundamental role in the observed electrical dysfunction.

Human sodium current voltage‐dependence at physiological temperature measured by coupling a patch‐clamp experiment to a mathematical model

“…Firstly, the Na + channel is assembled from the pore‐forming α‐subunit SCN5A and auxiliary β‐subunits, the latter interacting with the α‐subunit and modulating its voltage dependence (Balser, 1999). Moreover, alternatively spliced variants of β‐subunits are known to affect voltage dependence (Martinez‐Moreno et al., 2020). Inherited disorders including dilated cardiomyopathy are known to shift Na + current activation and inactivation (George, 2005; Nguyen et al., 2008).…”

Predicting functional effects of ion channel variants using new phenotypic machine learning methods

“…Our model predicts functional effect at the alpha subunit level, but does PLOS COMPUTATIONAL BIOLOGY not include data from auxiliary beta subunits (SCN1B-SCN3B) or other modulator proteins (e.g. FGF12) which may themselves affect channel expression levels, gating kinetics, or neuronal network activity [51][52][53]. The model is trained on data from whole-cell patch-clamp recordings of mammalian cells but includes no further information on experimental metadata.…”

Development and Characterization of the Mode-of-Action of Inhibitory and Agonist Peptides Targeting the Voltage-Gated Sodium Channel SCN1B/β1 Subunit

“…Brugada syndrome [35,52], and atrial fibrillation [34,53]. Importantly, the R85D and E87Q mutations near or within the βadp1 sequence can occur in both β1 and β1B.…”

“…This leads to the question of whether βadp1 could mimic a natural function of β1B in regulating β1-mediated cell adhesion, as well as modulating β1 RIP, since βadp1 is a sequence common to both β1B and β1. Interestingly, β1B loss of function mutations are implicated in various cardiac and neural pathologies [46], including Long QT-Syndrome [47], epilepsy [48, 49], Dravet syndromes [50, 51], Brugada syndrome [35, 52], and atrial fibrillation [34, 53]. Importantly, the R85D and E87Q mutations near or within the βadp1 sequence can occur in both β1 and β1B.…”