Abstract
The molecular approaches to distal renal tubular acidosis (dRTA) associated AE1 mutations lead us to understand the genetic and pathophysiological aspects of the acidification defects. An unanticipated high value of the urine-blood (U-B) PCO(2) after NaHCO(3) loading observed in a case of dRTA and southeast Asian ovalocytosis (SAO) might be from a mistarget of the AE1 to the luminal membrane of type A intercalated cells. The mutations of the AE1 gene resulted in SAO and also affected renal acidification function. Notwithstanding, after the NH4Cl loading in 20 individuals with SAO, the acidification in the distal nephron was normal. The presence of both SAO and G701D mutations of AE1 gene would explain the abnormal urinary acidification in the patients with the compound heterozogosity. In terms of the effect of the mutations on trafficking of AE1, truncated kidney isoform (kAE1) of wild-type showed a 'dominant-positive effect' in rescuing the recessive mutant kAE1 (S773P or G701D) trafficking to the plasma membrane, in contrast with the dominant mutant kAE1 (R589H) resulting in a 'dominant-negative effect' when heterodimerized with the wild-type kAE1. It is notable that the dominant mutants kAE1 (R901X or G609R) expression in MDCK cells clearly results in aberrant surface expression with some mutant protein appearing at the apical membrane. These might result in net bicarbonate secretion and increasing U-B PCO(2) in the distal nephron. The molecular physiological and genetic approaches have permitted identification of the molecular defects, predominantly in transporter proteins, and should in turn prompt development of novel therapeutic strategies.