Genetic Diseases of Acid-Base Transporters

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.