The association between familial distal renal tubular acidosis and mutations in the red cell anion exchanger (band 3, AE1) gene

In distal renal tubular acidosis (dRTA) the tubular secretion of hydrogen i on in the distal nephron is impaired, leading to the development of metabol ic acidosis, frequently accompanied by hypokalemia, nephrocalcinosis, and m etabolic bone disease. The condition can be familial, when it is usually in herited as an autosomal dominant, though there is a rarer autosomal recessi ve form associated with nerve deafness. It has been shown that the autosoma l dominant form of dRTA is associated with a defect in the anion exchanger (AE1) of the renal collecting duct intercalated cell. This transporter is a product of the same gene (AE1) as the erythrocyte anion exchanger, band 3. In this review we will look at the evidence for this association. Studies of genomic DNA from families with this disorder have shown, both by genetic linkage studies and by DNA sequencing, that affected individuals are heter ozygous for mutations in the AE1 gene whilst unaffected family members have a normal band 3 sequence. Mutations have been found in the region of propo sed helices 6 and 7 of the membrane domain of band 3 and involve amino acid s Arg-589 and Ser-613, and in the COOH-terminal domain of band 3. Studies o f red cell band 3 from these families have provided information on the effe ct these mutations have on the structure and function of erythrocyte band 3 . Expression studies of the erythroid and kidney isoforms of the mutant AE1 proteins, in Xenopus laevis oocytes, have shown that they retained chlorid e transport activity, suggesting that the disease in the dRTA families is n ot related simply to the anion transport activity of the mutated proteins. A possible explanation for the dominant effect of these mutant AE1 proteins in the kidney cell is that these mutations affect the targeting of AE1 fro m the basolateral to the apical membrane of the alpha-intercalated cell.