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 V-1 subunit B1 (associated with deafness) and the V-0 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 V-0 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.