Gitelman's variant of Barter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na–Cl cotransporter

Abstract

Maintenance of fluid and electrolyte homeostasis is critical for normal neuromuscular function. Bartter's syndrome is an autosomal recessive disease characterized by diverse abnormalities in electrolyte homeostasis including hypokalaemic metabolic alkalosis; Gitelman's syndrome represents the predominant subset of Bartter's patients having hypomagnesemia and hypocalciuria. We now demonstrate complete linkage of Gitelman's syndrome to the locus encoding the renal thiazide-sensitive Na-Cl cotransporter, and identify a wide variety of non-conservative mutations, consistent with loss of function alleles, in affected subjects. These findings demonstrate the molecular basis of Gitelman's syndrome. We speculate that these mutant alleles lead to reduced sodium chloride reabsorption in the more common heterozygotes, potentially protecting against development of hypertension.

Parvalbumine et régulation du transport ionique dans le tube contourné distal du rein

“…Les mécanismes de transport opérant dans le TCD sont perturbés dans le syndrome de Gitelman, une maladie autosomique récessive (prévalence 1/50 000) qui associe déplétion sodée, hypokaliémie, alcalose métabolique, hypomagnésémie et hypocalciurie. Le syndrome de Gitelman est causé par des mutations invalidantes du gène SLC12A3 codant pour le cotransporteur apical NCC [2]. L'inactivation de NCC induit une perte de sel et une contraction volémique, stimulant l'axe rénine-angiotensine-aldostérone et entraînant une réabsorption électro-génique de Na + dans le canal collecteur via le canal épithélial sodique ENaC.…”

Role of the alternative splice variant of NCC in blood pressure control

“…The molecular cloning of human NCC took place in 1996, showing that there exist three different isoforms of the protein as a result of alternative splicing of the SLC12A3 gene [18,21]. Simon et al .…”

“…Simon et al . reported an mRNA sequence encoding a 1,030 amino acid protein, which was NCC 1 [18]. Mastroianni et al .…”

“…Furthermore, over 180 loss-of-function mutations have been identified in the SLC12A3 gene, encoding NCC, in relation to Gitelman syndrome (OMIM 263,800) [14–16]. This is an autosomal recessive disease that is portrayed by hypocalciuria, hypomagnesemia, hypokalemic metabolic alkalosis, sodium wasting and lower blood pressure levels in comparison to their age-matched unaffected relatives [17,18]. …”

“…NCC isoforms 1 and 2 (NCC 1 and NCC 2 ), collectively termed NCC SV , are nine amino acids longer than the third isoform (NCC 3 ) [18–20]. In the present review, we aim to outline the newest findings on the molecular regulation of NCC SV and its role in renal salt handling in various (patho)physiological conditions.…”