Analysis of Single-Nucleotide Polymorphisms in Human Voltage-Gated Ion Channels

Voltage-gated ion channels (VGICs)
are one of the largest groups
of transmembrane proteins. Due to their major role in the generation
and propagation of electrical signals, VGICs are considered important
from a medical viewpoint, and their dysfunction is often associated
with Channelopathies. We identified disease-associated mutations and
polymorphisms in these proteins through mapping missense single-nucleotide
polymorphisms from the UniProt and ClinVar databases on their amino
acid sequence, considering their special topological and functional
characteristics. Statistical analysis revealed that disease-associated
SNPs are mostly found in the voltage sensor domain and the pore loop.
Both of these regions are extremely important for the activation and
ion conductivity of VGICs. Moreover, among the most frequently observed
mutations are those of arginine to glutamine, to histidine or to cysteine,
which can probably be attributed to the extremely important role of
arginine residues in the regulation of membrane potential in these
proteins. We suggest that topological information in combination with
genetic variation data can contribute toward a better evaluation of
the effect of currently unclassified mutations in VGICs. It is hoped
that potential associations with certain disease phenotypes will be
revealed in the future with the use of similar approaches.