Genetic causes and mechanisms of distal renal tubular acidosis

Nephrol Dial Transplant. 2012 Oct;27(10):3691-704. doi: 10.1093/ndt/gfs442.


The primary or hereditary forms of distal renal tubular acidosis (dRTA) have received increased attention because of advances in the understanding of the molecular mechanism, whereby mutations in the main proteins involved in acid-base transport result in impaired acid excretion. Dysfunction of intercalated cells in the collecting tubules accounts for all the known genetic causes of dRTA. These cells secrete protons into the tubular lumen through H(+)-ATPases functionally coupled to the basolateral anion exchanger 1 (AE1). The substrate for both transporters is provided by the catalytic activity of the cytosolic carbonic anhydrase II (CA II), an enzyme which is also present in the proximal tubular cells and osteoclasts. Mutations in ATP6V1B1, encoding the B-subtype unit of the apical H(+) ATPase, and ATP6V0A4, encoding the a-subtype unit, lead to the loss of function of the apical H(+) ATPase and are usually responsible for patients with autosomal recessive dRTA often associated with early or late sensorineural deafness. Mutations in the gene encoding the cytosolic CA II are associated with the autosomal recessive syndrome of osteopetrosis, mixed distal and proximal RTA and cerebral calcification. Mutations in the AE1, the gene that encodes the Cl(-)/HCO(3)(-) exchanger, usually present as dominant dRTA, but a recessive pattern has been recently described. Several studies have shown trafficking defects in the mutant protein rather than the lack of function as the major mechanism underlying the pathogenesis of dRTA from AE1 mutations.

Publication types

  • Editorial
  • Review

MeSH terms

  • Acid-Base Equilibrium / genetics
  • Acidosis, Renal Tubular / diagnosis
  • Acidosis, Renal Tubular / drug therapy
  • Acidosis, Renal Tubular / etiology
  • Acidosis, Renal Tubular / genetics*
  • Animals
  • Anion Exchange Protein 1, Erythrocyte / genetics
  • Carbonic Anhydrase II / genetics
  • Carbonic Anhydrases / deficiency
  • Carbonic Anhydrases / genetics
  • Disease Models, Animal
  • Genetic Testing
  • Hearing Loss / genetics
  • Humans
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Mutant Proteins / genetics
  • Mutation
  • Osteopetrosis / genetics
  • Urea Cycle Disorders, Inborn / genetics
  • Vacuolar Proton-Translocating ATPases / genetics


  • ATP6V1B1 protein, human
  • Anion Exchange Protein 1, Erythrocyte
  • Mutant Proteins
  • ATP6V0A4 protein, human
  • Vacuolar Proton-Translocating ATPases
  • Carbonic Anhydrase II
  • Carbonic Anhydrases

Supplementary concepts

  • Osteopetrosis with renal tubular acidosis