AUTOSOMAL-DOMINANT DISTAL RENAL TUBULAR-ACIDOSIS IS ASSOCIATED IN 3 FAMILIES WITH HETEROZYGOSITY FOR THE R589H MUTATION IN THE AE1 (BAND-3)CL- HCO3- EXCHANGER/

Distal renal tubular acidosis (dRTA) is characterized by defective uri nary acidification by the distal nephron. Cl-/HCO3- exchange mediated by the AE1 anion exchanger in the basolateral membrane of type A inter calated cells is thought to be an essential component of lumenal H+ se cretion by collecting duct intercalated cells. We evaluated the AE1 ge ne as a possible candidate gene for familial dRTA. We found in three u nrelated families with autosomal dominant dRTA that all clinically aff ected individuals were heterozygous for a single missense mutation enc oding the mutant AE1 polypeptide R589H, Patient red cells showed simil ar to 20% reduction in sulfate influx of normal 4,4'-diisothiocyanosti lbene-2,2'-disulfonic acid sensitivity and pH dependence. Recombinant kidney AE1 R589H expressed in Xenopus oocytes showed 20-50% reduction in Cl-/Cl- and Cl-/HCO3- exchange, but did not display a dominant nega tive phenotype for anion transport when coexpressed with wild-type AE1 , One apparently unaffected individual for whom acid-loading data were unavailable also was heterozygous for the mutation. Thus, in contrast to previously described heterozygous loss-of-function mutations in AE 1 associated with red cell abnormalities and apparently normal renal a cidification, the heterozygous hypomorphic AE1 mutation R589H is assoc iated with dominant dRTA and normal red cells.