Human genetic polymorphisms determine CLC-Kb glycosylation and current

A previous study using a rare genetic variant, demonstrated that the absence of glycosylation affects the function of ClC-Kb channels in the distal tubule and leads to Bartter/Gitelman Syndrome type III. However, the role of more common variants or single nucleotide polymorphisms (SNPs) is unknown. In cultured cells, we measured glycosylation and whole-cell currents of various CLCNKB constructs carrying five common SNPs, namely R27L, A214G, A287V, M562T, and K578E. We found that these SNPs influence both glycosylation and CLC-Kb currents. Our investigation of the CLCNKB A287V variant (present in more than half of individuals) revealed that this SNP restores glycosylation and current compared to the "wild-type" reference sequence. The other four variants in combination may also augment current by glycosylation-indepepdent mechanisms. This work has implications for regulation of blood pressure and hypertension whereby CLCNKB SNPs may account for differences in baseline sodium and chloride reabsorption.