Genetic Disorders of NaCl Transport in the Distal Convoluted Tubule

Abstract

The distal convoluted tubule (DCT) reabsorbs 5–10% of filtered Na, and is an important site for regulation of Na balance. Additionally, the amount and composition of the tubular fluid that leaves the DCT affects H and K secretion in more distal nephrin segments. Mutations in five genes whose products are expressed in the DCT demonstrate these points and help to define the mechanisms by which the DCT contributes to control of electrolyte balance and volume. Loss of function mutations in the apical thiazide-sensitive NaCl cotransporter and the basolateral K channel Kir4.1, and activating mutations in the Ca-sensing receptor cause a phenotypically similar salt wasting syndrome. Mutation in two recently identified kinases, WNK1 and WNK4 cause a salt-retaining syndrome through increased apical expression of NaCl cotransporter. Recent studies indicate that these genes are important not only for understanding the physiology of the distal nephron, but that they and others may also contribute to blood pressure variation in the general population.

Gitelman's syndrome: a pathophysiological and clinical update

“…This mutation in NCC activity causes less NaCl reabsorption in the DCT, such that more NaCl is present in the more distal nephron. The consequent volume depletion results in increased renin-aldosterone, ENaC activity, potassium wasting [15,16]. Hypocalciuria, a marker of GS is the result of increased proximal tubule passive calcium reabsorption secondary to extracellular volume contraction (ECV).…”

“…Other authors described that the majority of GS patients are compound heterozygotes, carrying two different mutations on the parental alleles of SLC12A3 [3,[15][16][17]. A minority of GS patients with no evidence for diseasecausing mutations in SLC12A3 have been shown to carry mutations in CLCNKB encoding the chloride channel ClCKb, located in the basolateral membrane of cells of the thick ascending loop of Henle [1,21].…”

Basolateral membrane K+channels in renal epithelial cells

“…Subsequently, the physiological roles of these proteins in transepithelial ion/solute transport have been elucidated, resulting in the identification of many diseases of epithelia caused by mutations of ion channels and transporters. These include various renal tubulopathies, including Bartter's syndrome (42,64,136), Gitelman's syndrome (37,88), EAST syndrome (for infant Epilepsy, severe Ataxia, moderate Sensorineural deafness and renal salt wasting Tubulopathy) (2,11), SeSAME syndrome (for Seizures, Sensorineural deafness, Ataxia, Mental retardation and Electrolyte imbalance) (107,115,137), Liddle's disease (14,118), nephrogenic diabetes insipidus (10,80), and renal tubular acidosis syndrome (134).…”