Kidney AE1 (kAE1) is a glycoprotein responsible for the electroneutral exchange of chloride for bicarbonate, promoting the reabsorption of bicarbonate into the blood by -intercalated cells of the collecting tubule. Mutations occurring in the gene encoding kAE1 can induce defects in urinary acidification resulting in distal renal tubular acidosis (dRTA). We expressed two kAE1 dRTA mutants, A858D, a mild dominant mutation and V850, a recessive mutation, in epithelial Madin-Darby canine kidney (MDCK) cells. Individuals heterozygous with wild-type (WT) kAE1 either did not display any symptoms of dRTA (V850/WT) or displayed a mild incomplete form of dRTA (A858D/WT), while compound heterozygotes (V850/A858D) had dRTA. We found that the A858D mutant was slightly impaired in the endoplasmic reticulum (ER) exit but could target to the basolateral membrane of polarized MDCK cells. Despite an altered binding to an inhibitor affinity resin, anion transport assays showed that A858D mutant was functional at the cell surface. The V850 mutant showed altered binding to the affinity resin but was predominantly retained in the ER, resulting in undetectable AE1 expression at the basolateral membrane. When co-expressed in MDCK cells, the WT protein, and to a less extent A858D mutant, enhanced the cell surface expression of the V850 mutant. The V850 mutant also affected the cell surface expression of the A858D mutant. Compound heterozygous (A858D/V850) patients likely possess a decreased amount of functional anion exchangers at the basolateral membrane of their -intercalated cells, resulting in impaired bicarbonate transport into the blood and defective acid transport into the urine.