Genetic diseases of acid-base transporters

Annu Rev Physiol. 2002;64:899-923. doi: 10.1146/annurev.physiol.64.092801.141759.


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.

Publication types

  • Review

MeSH terms

  • Acid-Base Equilibrium / genetics*
  • Acidosis, Renal Tubular / genetics*
  • Acidosis, Renal Tubular / metabolism*
  • Anion Exchange Protein 1, Erythrocyte / genetics
  • Anion Exchange Protein 1, Erythrocyte / metabolism
  • Carbonic Anhydrases / genetics
  • Carbonic Anhydrases / metabolism
  • Chloride Channels / genetics
  • Chloride Channels / metabolism
  • Humans
  • Sodium-Bicarbonate Symporters / genetics
  • Sodium-Bicarbonate Symporters / metabolism
  • Vacuolar Proton-Translocating ATPases / genetics
  • Vacuolar Proton-Translocating ATPases / metabolism


  • Anion Exchange Protein 1, Erythrocyte
  • Chloride Channels
  • Sodium-Bicarbonate Symporters
  • Vacuolar Proton-Translocating ATPases
  • Carbonic Anhydrases