Point mutations involved in red cell stomatocytosis convert the electroneutral anion exchanger 1 to a nonselective cation conductance.

The anion exchanger 1 (AE1) is encoded by the SLC4A1 gene and catalyzes the electroneutral anion exchange across cell plasma membrane. It is the most abundant transmembrane protein expressed in red cell where it is involved in CO(2) transport. Recently, 4 new point mutations of SLC4A1 gene have been described leading to missense mutations in the protein sequence (L687P, D705Y, S731P, or H734R). These point mutations were associated with hemolytic anemia, and it was shown that they confer a cation transport feature to the human AE1. Facing this unexpected property for an electroneutral anion exchanger, we have studied the transport features of mutated hAE1 by expression in xenopus oocytes. Our results show that the point mutations of hAE1 convert the electroneutral anion exchanger to a cation conductance: the exchangers are no longer able to exchange Cl(-) and HCO(3)(-), whereas they transport Na(+) and K(+) through a conductive mechanism. These data shed new light on transport mechanisms showing the tiny difference, in terms of primary sequence, between an electroneutral exchange and a conductive pathway.