Defects in processing and trafficking of the AE1 Cl-/HCO3- exchanger associated with inherited distal renal tubular acidosis.
Distal renal tubular acidosis (dRTA) results from impaired urinary acidification by the renal collecting duct. Acquired dRTA can be secondary to diverse pathological processes, including diabetic, ischemic, fibrosing, or immunological processes; less frequently it presents as a familial disorder with either an autosomal recessive or dominant pattern of transmission. Mutations in the SLC4A1/AE1/band 3 Cl(-)/HCO(3)(-) exchanger gene have been identified as causes for both dominant and recessive forms of dRTA. These mutations comprise a group almost entirely distinct from the SLC4A1 mutations that underlie the familial hemolytic anemia of hereditary spherocytosis. Why does one group of mutations express almost exclusively an isolated erythroid phenotype, whereas the second group of mutations expresses almost exclusively a phenotype explicable entirely by defective function of renal collecting duct type A intercalated cells? This review summarizes current research addressing this central question in the pathobiology of inherited dRTA associated with mutations in the SLC4A1 gene. Studying dRTA-associated mutant AE1 polypeptides can provide novel insights into the biology of the intercalated cell and the collecting duct as well as more generally into mechanisms by which epithelial cells generate and maintain functional polarity.
Shayakul
Chairat
C
Renal Unit, Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Alper
Seth L
SL
D000141:Acidosis, Renal Tubular / Q000235:genetics* / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D005799:Genes, Dominant; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D013103:Spherocytosis, Hereditary / Q000235:genetics
D001457:Anion Exchange Protein 1, Erythrocyte; D008565:Membrane Proteins