Cation transport activity of anion exchanger 1 mutations found in inherited distal renal tubular acidosis.

Anion exchanger 1 (AE1) is encoded by SLC4A1 and mediates electroneutral anion exchange across cell membranes. It is the most abundant protein in the red cell membrane, but it is also found in the basolateral membrane of renal alpha-intercalated cells, where it is required for normal urinary acidification. Recently, four point mutations in red cell AE1 have been described that convert the anion exchanger to a cation conductance. SLC4A1 mutations can also cause type 1 hypokalemic distal renal tubular acidosis (dRTA). We investigated the properties of four dRTA-associated AE1 mutations (R589H, G609R, S613F, and G701D) by heterologous expression in Xenopus laevis oocytes. Although these AE1 mutants are functional anion exchangers, unlike the red cell disease mutants, we found that they also demonstrated a cation leak. We found a large cation leak in the G701D mutant. This mutant normally requires coexpression with glycophorin A for surface membrane expression in red blood cells and oocytes. However, we found that coexpressing wild-type kidney AE1 with G701D in oocytes still caused a cation leak, consistent with heterodimerized G701D reaching the cell membrane and retaining its cation conductance property. These findings have potential structural and functional implications for AE1, and they indicate that while anion exchange and cation conductance properties are distinct, they can coexist.