Section of Cell Biology and Biophysics, Department of Biology, School of Sciences , National and Kapodistrian University of Athens , Panepistimiopolis, Athens 15701 , Greece.
J Proteome Res. 2019 May 3;18(5):2310-2320. doi: 10.1021/acs.jproteome.9b00121. Epub 2019 Apr 1.
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.
电压门控离子通道（VGICs）是跨膜蛋白中最大的一类。由于它们在电信号的产生和传播中起着重要作用，因此从医学角度来看，它们非常重要，其功能障碍通常与通道病有关。我们通过将 UniProt 和 ClinVar 数据库中的错义单核苷酸多态性映射到它们的氨基酸序列上，来识别这些蛋白质中的疾病相关突变和多态性，考虑到它们特殊的拓扑和功能特征。统计分析表明，疾病相关的 SNP 主要存在于电压传感器域和孔环中。这两个区域对于 VGIC 的激活和离子导电性都非常重要。此外，最常观察到的突变是精氨酸突变为谷氨酰胺、组氨酸或半胱氨酸，这可能归因于精氨酸残基在这些蛋白质中调节膜电位的极其重要作用。我们认为，拓扑信息与遗传变异数据的结合，可以有助于更好地评估 VGIC 中目前未分类突变的影响。希望未来能够使用类似的方法揭示与某些疾病表型的潜在关联。
