Comparing Mutability of Clinically Significant Voltage-Gated Sodium Channel Subunits (P4-1.003)

Abstract

<h3>Objective:</h3> The objective of this project was to compare the mutability profile of the clinically significant beta1 and beta2 subunits of the voltage-gated sodium channel. <h3>Background:</h3> The voltage-gated sodium channel (VGSC) plays a role in generating action potentials in excitable tissues. Mutations in VGSC subunits, including the beta1 and beta3 subunits, are associated with diseases like epilepsy and cardiac arrhythmia. <h3>Design/Methods:</h3> We compared amino acid variants in the beta1 and beta2 subunits found in patients and the general population within the gnomAD database, and cancer cell variants from the cBioPortal Cancer Genomics database. We also reviewed variants for both subunits in cancer cells using the cBioPortal database. <h3>Results:</h3> Based on the data from gnomAD both subunits have variants reported in a similar percentage of the primary sequence (39.4% for beta1 and 39% for beta3), but pathogenic variants are more common in beta1 (5% of residues) than beta3 (1.86%, <i>p</i>=0.065). In 43789 patients with sequencing information for the genes SCN1B and SCN3B (coding for beta1 and beta3, respectively) 2.2% had non-synonymous variants in beta1 and 3.3% in beta3 (<i>p</i>=0.002). A minority of residues within each subunit (6.8% in beta1 and 9.76% in beta3) had a variant reported in cancer cells (<i>p</i>=.276). 4.58% of beta1 and 6.51% of beta3 residues have variants reported both in human and cancer cells. Of the residues reported with pathogenic variants in beta1, one (p.C21) had a variant found in cancer cells, and there were none for beta3. <h3>Conclusions:</h3> Our results suggest that the residues with pathogenic variants are a non-overlapping set between the two subunits, and might represent targets for their specialized function. In cancer cells, beta3 had a higher mutation load than beta1, suggesting different evolutionary pressures on both proteins. One limitation of our study is that we only focused on the main splice variant of <i>SCN1B</i> and <i>SCN3B</i> genes. <b>Disclosure:</b> Dr. Patino has received publishing royalties from a publication relating to health care. Dr. Patino has received personal compensation in the range of $0-$499 for serving as a project mentor with Manning Publications. Mr. Armstrong has nothing to disclose.