Human anion exchanger1 mutations and distal renal tubular acidosis.

The human anion exchanger 1 (AE1 or SLC4A1) gene encodes anion exchanger 1 (or band 3) protein in erythrocytes and in alpha-intercalated cells of the kidney. Thus, AE1 mutations show pleiotrophic effects resulting in two distinct and seemingly unrelated defects, an erythrocyte abnormality and distal renal tubular acidosis (dRTA). Southeast Asian ovalocytosis (SAO), a well-known red blood cell (RBC) defect, which is widespread in Southeast Asian regions, is caused by AE1 mutation due to a deletion of 27 base pairs in codons 400-408 (delta400-408) leading to an in-frame 9 amino-acid loss in the protein. Co-existence of SAO and dRTA is usually not seen in the same individual. However, the two conditions can co-exist as the result of compound heterozygosities between delta400-408 and other mutations. The reported genotypes include delta400-408/G701D, delta400-408/R602H, delta400-408/deltaV850, and delta400-408/A858D. The presence of dRTA, with or without RBC abnormalities, may occur from homozygous or compound heterozygous conditions of recessive AE1 mutations (eg G701D/G701D, V488M/V488M, deltaV850/deltaV850, deltaV850/A858D, G701D/S773P) or heterozygous dominant AE1 mutations (eg R598H, R589C, R589S, S613F, R901X). Codon 589 of this gene seems to be a 'mutational hot-spot' since repeated mutations at this codon occurring in different ethnic groups and at least two de novo (R589H and R589C) mutations have been observed. Therefore, AE1 mutations can result in both recessive and dominant dRTA, possibly depending on the position of the amino acid change in the protein. As several mutant AE1 proteins still maintain a significant anion transport function but are defective in targeting to the cell surface, impaired intracellular trafficking of the mutant AE1 is an important molecular mechanism involved in the pathogenesis of dRTA associated with AE1 mutations.