title: Genetic diseases of acid-base transporters.
abstract: Genetic disorders of acid-base transporters involve plasmalemmal and organellar transporters of H(+), HCO3(-), and Cl(-). Autosomal-dominant and -recessive forms of distal renal tubular acidosis (dRTA) are caused by mutations in ion transporters of the acid-secreting Type A intercalated cell of the renal collecting duct. These include the AE1 Cl(-)/HCO3(-) exchanger of the basolateral membrane and at least two subunits of the apical membrane vacuolar (v)H(+)-ATPase, the V1 subunit B1 (associated with deafness) and the V0 subunit a4. Recessive proximal RTA with ocular disease arises from mutations in the electrogenic Na(+)-bicarbonate cotransporter NBC1 of the proximal tubular cell basolateral membrane. Recessive mixed proximal-distal RTA accompanied by osteopetrosis and mental retardation is associated with mutations in cytoplasmic carbonic anhydrase II. The metabolic alkalosis of congenital chloride-losing diarrhea is caused by mutations in the DRA Cl(-)/HCO3(-) exchanger of the ileocolonic apical membrane. Recessive osteopetrosis is caused by deficient osteoclast acid secretion across the ruffled border lacunar membrane, the result of mutations in the vH(+)-ATPase V0 subunit or in the CLC-7 Cl(-) channel. X-linked nephrolithiasis and engineered deficiencies in some other CLC Cl(-) channels are thought to represent defects of organellar acidification. Study of acid-base transport disease-associated mutations should enhance our understanding of protein structure-function relationships and their impact on the physiology of cell, tissue, and organism.
authors.affiliation: Molecular Medicine and Renal Units, Beth Israel Deaconess Medical Center, Department of Medicine and Cell Biology, Harvard Medical School Boston, Massachusetts 02215, USA. salper@caregroup.harvard.edu
authors.forename: Seth L
authors.initials: SL
authors.lastname: Alper
mesh_terms: D000136:Acid-Base Equilibrium / Q000235:genetics*; D000141:Acidosis, Renal Tubular / Q000235:genetics* / Q000378:metabolism*; D001457:Anion Exchange Protein 1, Erythrocyte / Q000235:genetics / Q000378:metabolism; D002256:Carbonic Anhydrases / Q000235:genetics / Q000378:metabolism; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism; D006801:Humans; D027982:Sodium-Bicarbonate Symporters / Q000235:genetics / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism
chemical_list: D001457:Anion Exchange Protein 1, Erythrocyte; D018118:Chloride Channels; D027982:Sodium-Bicarbonate Symporters; D025262:Vacuolar Proton-Translocating ATPases; D002256:Carbonic Anhydrases