Compound mutations in human anion exchanger 1 are associated with complete distal renal tubular acidosis and hereditary spherocytosis.

Missense, nonsense, and frameshift mutations in the human anion exchanger 1 have been associated with inherited distal renal tubular acidosis and hereditary spherocytosis. These two disorders, however, are almost always mutually exclusive. We have found an important and unusual exception: a novel combination of heterozygous E522K and G701D mutations in the anion exchanger 1 manifested as complete distal renal tubular acidosis and severe hereditary spherocytosis in an affected patient. Analysis of protein trafficking and subcellular localization of the wild-type kidney isoform of human anion exchanger 1 and these mutants transfected into MDCK cells showed they formed homodimers or heterodimers with each other. Homodimers of the wild-type and E522K mutant were found at the plasma membrane, whereas the G701D mutant largely remained in the cytoplasm. Heterodimers of either E522K or G701D and the wild-type exchanger were located in the plasma membrane, whereas E522K/G701D heterodimers remained in the cytoplasm. Our study shows that the compound E522K/G701D mutation of human anion exchanger 1 causes a trafficking defect in kidney cells, and this may explain the complete distal renal tubular acidosis of the patient.