Autosomal recessive distal renal tubular acidosis associated with Southeast Asian ovalocytosis

Background. A defect in the anion exchanger 1 (AE1) of the basolateral memb rane of typo A intercalated cells in the renal collecting duct may result i n a failure to maintain a cell-to-lumen H+ gradient, leading to distal rena l tubular acidosis (dRTA). Thus, dRTA may occur in Southeast Asian ovalocyt osis (SAO), a common AE1 gene abnormality observed in Southeast Asia and Me lanesia. Our study investigated whether or not this renal acidification def ect exists in individuals with SAO. Methods. Short and three-day NH4Cl loading tests were per formed in 20 indi viduals with SAO and in two subjects, including their families, with both S AO and dRTA. Mutations of AE1 gene in individuals with SAO and members of t he two families were also studied. Results. Renal acidification in the 20 individuals with SAO and in the pare nts of the two families was normal. However, the two clinically affected in dividuals with SAO and dRTA had compound heterozygosity of 27 bp deletion i n exon 11 and missense mutation G701D resulting from a CGG-->CAG substituti on in exon 17 of the AE1 gene. Red cells of the two subjects with dRTA and SAO and the family members with SAO showed an approximate 40% reduction in sulfate influx with normal 4,4'-di-isothiocyanato-stilbene-2,2'-disulfonic acid sensitivity and pH dependence. Conclusion. These findings suggest that compound heterozygosity of abnormal AE1 genes causes autosomal recessive dRTA in SAO.