title: Compound mutations in human anion exchanger 1 are associated with complete distal renal tubular acidosis and hereditary spherocytosis.
abstract: 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.
authors.affiliation: Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors.forename: Yu-Hsiang
authors.initials: YH
authors.lastname: Chang
authors.forename: Chen-Fu
authors.initials: CF
authors.lastname: Shaw
authors.forename: Shu-Huei
authors.initials: SH
authors.lastname: Jian
authors.forename: Kai-Hsien
authors.initials: KH
authors.lastname: Hsieh
authors.forename: Yee-Hsuan
authors.initials: YH
authors.lastname: Chiou
authors.forename: Pei-Jung
authors.initials: PJ
authors.lastname: Lu
mesh_terms: D000141:Acidosis, Renal Tubular / Q000235:genetics*; D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000235:genetics*; D002460:Cell Line; D004285:Dogs; D006801:Humans; D050505:Mutant Proteins / Q000378:metabolism; D020125:Mutation, Missense; D055503:Protein Multimerization / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D013103:Spherocytosis, Hereditary / Q000235:genetics*; D014162:Transfection
chemical_list: D001457:Anion Exchange Protein 1, Erythrocyte; D050505:Mutant Proteins