Novel AE1 mutations in recessive distal renal tubular acidosis - Loss-of-function is rescued by glycophorin A

The AE1 gene encodes band 3 Cl-/HCO3- exchangers that are expressed both in the erythrocyte and in the acid-secreting, type A intercalated cells of th e kidney. Kidney AE1 contributes to urinary acidification by providing the major exit route for HCO3- across the basolateral membrane, Several AE1 mut ations cosegregate with dominantly transmitted nonsyndromic renal tubular a cidosis (dRTA), However, the modest degree of in vitro hypofunction exhibit ed by these dRTA-associated mutations fails to explain the disease phenotyp e in light of the normal urinary acidification associated with the complete loss-of-function exhibited by AE1 mutations linked to dominant spherocytos is. We report here novel AE1 mutations linked to a recessive syndrome of dR TA and hemolytic anemia in which red cell anion transport is normal. Both a ffected individuals were triply homozygous for two benign mutations M31T an d K56E and for the loss-of-function mutation, G701D, AE1 G701D loss-of-func tion was accompanied by impaired trafficking to the Xenopus oocyte surface, Coexpression with AE1 G701D of the erythroid AE1 chaperonin, glycophorin A , rescued both AE1-mediated Cl- transport and AE1 surface expression in ooc ytes, The genetic and functional data both suggest that the homozygous AE1 G701D mutation causes recessively transmitted dRTA in this kindred with app arently normal erythroid anion transport.