Unraveling the molecular basis of hereditary renal tubular acidosis

Abstract

Renal tubular acidosis (RTA) is a clinical syndrome of disordered renal acidification in which the kidney fails to maintain a normal plasma concentration of HCO3 − in the setting of a normal rate of acid load from diet and metabolism. Most RTA in children is hereditary. Hereditary RTA can be classified into several groups on clinical and pathophysiological grounds. Recent progress in molecular biological analyses is unraveling the molecular basis of hereditary RTA. Mutations in the kidney type Na+/HCO3 − cotransporter gene (SLC4A4) cause permanent isolated proximal RTA with ocular abnormalities. Mutations in the carbonic anhydrase II gene lead to osteopetrosis, RTA (proximal RTA, distal RTA, or combined proximal and distal RTA), cerebral calcification, and mental retardation. Mutations in the gene (SLC4A1) encoding the Cl−/HCO3 − exchanger produce autosomal dominant distal RTA. However, mutations in SLC4A1 also link to a recessive syndrome of distal RTA with hemolytic anemia (Southeast Asian ovalocytosis) in Thailand. The phenotype of this distal RTA in Thailand is very close to that of autosomal dominant distal RTA in other countries. In contrast, autosomal recessive distal RTA, which is phenotypically heterogeneous, is a more severe disorder than autosomal dominant distal RTA. Mutations in ATP6B1, the B1-subunit of the apical H+-adenosine triphosphatase (ATPase) mediating distal nephron acid secretion, cause distal RTA with progressive bilateral sensorineural hearing loss. Moreover, mutations in ATP6N1B, encoding a tubular apical H+-ATPase 116-kD subunit, are reported to lead to distal dRTA with preserved hearing. These results can help in the further understanding of the molecular basis of hereditary RTAs and can help to characterize the clinical and genetic manifestations of these disorders.