Sodium channel protein alpha subunit genomics: building an integrated knowledgebase to translate between family members

The sodium channel alpha proteins consist of ten homologous human proteins (SCN1A, SCN2A, SCN3A, SCN4A, SCN5A, SCN7A, SCN8A, SCN9A, SCN10A, SCN11A), many involved in various human physiological pathways and clinical disorders/syndromes. Many human variants connected to these genes remain uncertain for human disease. To better support the understanding of challenging human variants, we have built an ortholog database of the alpha subunit proteins for the sodium channel. We combined 1,680 vertebrate species sequences of family members, protein modeling, molecular dynamic simulation of lipid embedded protein, screening of human variants (gnomAD, ClinVar, Geno2MP), and analysis of a large number of human RNAseq and single-cell RNA-seq to understand the function of each amino acid in the human proteins and how the amino acids are conserved across family members to contribute to sodium channel functions within diverse cells of human. There are 610 amino acids conserved across the alpha subunit family, representing the most conserved amino acids for each member. These amino acids drive the structural fold, membrane interactions, and channel opening. A cluster of amino acids is conserved between a subset of family members that defines subclusters of alpha subunit proteins. Expression analysis of each member reveals clusters of members co-expressed in various cells, where heart and brain datasets show the specificity of cell types that contribute to genotype-to-phenotype associations of each member. Further, to support variant characterizations, the ortholog alignment data provides a unique ability to discover loss vs. gain of function variants found between members, allowing for known pathogenic variants of one member to aid in the characterization of another member's uncertain variants. For example, a clinical variant of SCN8A linked to seizures was supported as loss-of-function through variants within SCN1A (epilepsy), SCN2A (seizures), SCN4A (Familial hyperkalemic periodic paralysis), and SCN5A (Brugada syndrome). Overall, we show an exciting and promising new tool for ortholog genomic mapping that can support clinical variant insights into physiological outcomes (genotype-to-phenotype relationship), which should be applied to other cellular ion channels and transporters. This research was funded by the Gerber Foundation (to JWP), National Institutes of Health (K01ES025435 to JWP), and Michigan State University. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.