FAMILIAL DISTAL RENAL TUBULAR-ACIDOSIS IS ASSOCIATED WITH MUTATIONS IN THE RED-CELL ANION-EXCHANGER (BAND-3, AE1) GENE

All affected patients in four families with autosomal dominant familia l renal tubular acidosis (dRTA) were heterozygous for mutations in the ir red cell HCO3-/Cl- exchanger, band 3 (AE1, SLC4A1) genes, and these mutations were not found in any of the nine normal family members stu died. The mutation Arg(589)-->His was present in two families, while A rg(589)-->Cys and Ser613-->Phe changes were found in the other familie s. Linkage studies confirmed the co-segregation of the disease with a genetic marker close to AE1. The affected individuals with the Ar-589 mutations had reduced red cell sulfate transport and altered glycosyla tion of the red cell band 3 N-glycan chain. The red cells of individua ls with the Ser(613)-->Phe mutation had markedly increased red cell su lfate transport but almost normal red cell iodide transport. The eryth roid and kidney isoforms of the mutant band 3 proteins were expressed in Xenopus oocytes and all showed significant chloride transport activ ity. We conclude that dominantly inherited dRTA is associated with mut ations in band 3; but both the disease and its autosomal dominant inhe ritance are not related simply to the anion trans; port activity of th e mutant proteins.