Human and murine phenotypes associated with defects in cation-chloride cotransport

Annu Rev Physiol. 2002;64:803-43. doi: 10.1146/annurev.physiol.64.081501.155847.

Abstract

The diuretic-sensitive cotransport of cations with chloride is mediated by the cation-chloride cotransporters, a large gene family encompassing a total of seven Na-Cl, Na-K-2Cl, and K-Cl cotransporters, in addition to two related transporters of unknown function. The cation-chloride cotransporters perform a wide variety of physiological roles and differ dramatically in patterns of tissue expression and cellular localization. The renal-specific Na-Cl cotransporter (NCC) and Na-K-2Cl cotransporter (NKCC2) are involved in Gitelman and Bartter syndrome, respectively, autosomal recessive forms of metabolic alkalosis. The associated phenotypes due to loss-of-function mutations in NCC and NKCC2 are consistent, in part, with their functional roles in the distal convoluted tubule and thick ascending limb, respectively. Other cation-chloride cotransporters are positional candidates for Mendelian human disorders, and the K-Cl cotransporter KCC3, in particular, may be involved in degenerative peripheral neuropathies linked to chromosome 15q14. The characterization of mice with both spontaneous and targeted mutations of several cation-chloride cotransporters has also yielded significant insight into the physiological and pathophysiological roles of several members of the gene family. These studies implicate the Na-K-2Cl cotransporter NKCC1 in hearing, salivation, pain perception, spermatogenesis, and the control of extracellular fluid volume. Targeted deletion of the neuronal-specific K-Cl cotransporter KCC2 generates mice with a profound seizure disorder and confirms the central role of this transporter in modulating neuronal excitability. Finally, the comparison of human and murine phenotypes associated with loss-of-function mutations in cation-chloride cotransporters indicates important differences in physiology of the two species and provides an important opportunity for detailed physiological and morphological analysis of the tissues involved.

Publication types

  • Review

MeSH terms

  • Animals
  • Bartter Syndrome / genetics
  • Bartter Syndrome / metabolism
  • Humans
  • Kidney Diseases / genetics
  • Kidney Diseases / metabolism
  • Nervous System Diseases / genetics
  • Nervous System Diseases / metabolism
  • Phenotype
  • Sodium Chloride Symporters
  • Sodium-Potassium-Chloride Symporters / genetics*
  • Sodium-Potassium-Chloride Symporters / metabolism*
  • Symporters / genetics
  • Symporters / metabolism

Substances

  • SLC12A6 protein, human
  • Sodium Chloride Symporters
  • Sodium-Potassium-Chloride Symporters
  • Symporters
  • potassium-chloride symporters