Abstract
Variants implicated in childhood epilepsy have been identified in all four voltage-gated sodium channels that initiate action potentials in the central nervous system. Previous research has focused on the functional effects of particular variants within the most studied of these channels (NaV1.1, NaV1.2 and NaV1.6); however, there have been few comparative studies across channels to infer the impact of mutations in patients with epilepsy. Here we compare patterns of variation in patient and public databases to test the hypothesis that regions of known functional significance within voltage-gated sodium (NaV) channels have an increased burden of deleterious variants. We assessed mutational burden in different regions of the Nav channels by (1) performing Fisher exact tests on odds ratios to infer excess variants in domains, segments, and loops of each channel in patient databases versus public "control" databases, and (2) comparing the cumulative distribution of variant sites along DNA sequences of each gene in patient and public databases (i.e., independent of protein structure). Patient variant density was concordant among channels in regions known to play a role in channel function, with statistically significant higher patient variant density in S4-S6 and DIII-DIV and an excess of public variants in SI-S3, DI-DII, DII-DIII. On the other hand, channel-specific patterns of patient burden were found in the NaV1.6 inactivation gate and NaV1.1 S5-S6 linkers, while NaV1.2 and NaV1.6 S4-S5 linkers and S5 segments shared patient variant patterns that contrasted with those in NaV1.1. These different patterns may reflect different roles played by the NaV1.6 inactivation gate in action potential propagation, and by NaV1.1 S5-S6 linkers in loss of function and haploinsufficiency. Interestingly, NaV1.2 and NaV1.6 both lack amino acid substitutions over significantly long stretches in both the patient and public databases suggesting that new mutations in these regions may cause embryonic lethality or a non-epileptic disease phenotype.
Highlights
Variants in all four brain-expressed voltage-gated sodium channels, NaV1.1, NaV1.2, NaV1.3, and NaV1.6, have been associated with epilepsy [1,2,3]
The percent of amino acid sequence difference among all three channels with the majority of regions having less than 30% divergence and only a handful of regions having higher than 30% divergence in the amino acid sequence for all three channels
Voltage-gated sodium (NaV) channels are responsible for the initiation and propagation of action potentials and are specialized for electrical signaling
Summary
Variants in all four brain-expressed voltage-gated sodium channels, NaV1.1, NaV1.2, NaV1.3, and NaV1.6, have been associated with epilepsy [1,2,3]. NaV1.1 is predominantly localized to the proximal dendrites and soma of excitatory neurons, and the axon-initiating segment (AIS) of fast-spiking parvalbumin-positive inhibitory neurons. This channel is believed to play a major role in controlling network excitability through the activation of inhibitory circuits [1]. Localized in dendrites and soma, NaV1.2 is expressed in the proximal AIS and in axons of unmyelinated neurons [1] This channel is predominantly expressed in the neocortex and hippocampus in excitatory neurons, yet has been reported in somatostatin-positive inhibitory interneurons [3]. Having a broad range of severity [5], variants in NaV1.6 were initially found to be associated with an epileptic encephalopathy (EIEE13) characterized by intellectual disability and developmental delay [6]
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