Band 3 mutations, renal tubular acidosis and South-East Asian ovalocytosis in Malaysia and Papua New Guinea: loss of up to 95% band 3 transport in red cells

We describe three mutations of the red-cell anion exchanger band 3 (AE1, SLC4A1) gene associated with distal renal tubular acidosis (dRTA) in families from Malaysia and Papua New Guinea: Gly(701)-->Asp (G701D), Ala(858)-->Asp (A858D) and deletion of Val(850) (Delta V850). The mutations A858D and Delta V850 are novel; all three mutations seem to be restricted to South-East Asian populations. South-East Asian ovalocytosis (SAO), resulting from the band 3 deletion of residues 400-408, occurred in many of the families but did not itself result in dRTA. Compound heterozygotes of each of the dRTA mutations with SAO all had dRTA, evidence of haemolytic anaemia and abnormal red-cell properties. The A858D mutation showed dominant inheritance and the recessive Delta V850 and G701D mutations showed a pseudo-dominant phenotype when the transport-inactive SAO allele was also present. Red-cell and Xenopus oocyte expression studies showed that the Delta V850 and A858D mutant proteins have greatly decreased anion transport when present as compound heterozygotes (Delta V850/A858D, Delta V850/SAO or A858D/SAO). Red cells with A858D/SAO had only 3 %, of the SO42- efflux of normal cells, the lowest anion transport activity so far reported for human red cells. The results suggest dRTA might arise by a different mechanism for each mutation. We confirm that the G701D mutant protein has an absolute requirement for glycophorin A for movement to the cell surface. We suggest that the dominant A858D mutant protein is possibly mis-targeted to an inappropriate plasma membrane domain in the renal tubular cell, and that the recessive Delta V850 mutation might give dRTA because of its decreased anion transport activity.