Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III

Abstract

Analysis of patients with inherited hypokalaemic alkalosis resulting from salt-wasting has proved fertile ground for identification of essential elements of renal salt homeostasis and blood-pressure regulation. We now demonstrate linkage of this phenotype to a segment of chromosome 1 containing the gene encoding a renal chloride channel, CLCNKB. Examination of this gene reveals loss-of-function mutations that impair renal chloride reabsorption in the thick ascending limb of Henle's loop. Mutations in seventeen kindreds have been identified, and they include large deletions and nonsense and missense mutations. Some of the deletions are shown to have arisen by unequal crossing over between CLCNKB and the nearby related gene, CLCNKA. Patients who harbour CLCNKB mutations are characterized by hypokalaemic alkalosis with salt-wasting, low blood pressure, normal magnesium and hyper- or normocalciuria; they define a distinct subset of patients with Bartter's syndrome in whom nephrocalcinosis is absent. These findings demonstrate the critical role of CLCNKB in renal salt reabsorption and blood-pressure homeostasis, and demonstrate the potential role of specific CLCNKB antagonists as diuretic antihypertensive agents.

Genetics of arterial hypertension and hypotension

“…A third variant of Bartter's syndrome is linked to inactivating mutations in the renal chloride channel CLCNKB ( Fig. 11; Simon et al 1997). The epithelial chloride channels CLCNKA and CLCNKB are heterodimers that require a second subunit, termed Barttin, for full activity.…”

Differential diagnosis of Bartter syndrome, Gitelman syndrome, and pseudo–Bartter/Gitelman syndrome based on clinical characteristics

“…BS and GS are reportedly caused by mutations in genes encoding ion transporters or channels, leading directly or indirectly to loss of function. [1][2][3][4][5][6] These genes include SLC12A1, which encodes the apical furosemide-sensitive Na-K-2Cl cotransporter 2 ; KCNJ1, which encodes the apical renal outer medullary potassium channel 3 ; CLCNKB, which encodes the basolateral chloride channel Kb (expressed in the thick ascending limb of Henle's loop and in the distal convoluted tubule) 1,7 ; and BSND, which encodes barttin, a subunit of chloride channels Ka and Kb. Mutations in these genes lead to types I-IV BS, respectively.…”

Rare independent mutations in renal salt handling genes contribute to blood pressure variation

“…Bartter's syndrome features massive renal salt wasting and hypotension, often resulting in neonatal death. It is caused by recessive loss of function mutations in any of 4 genes required for normal renal NaCl reabsorption [12][13][14][15] . These include the Na-K-2Cl cotransporter SLC12A1 and the inward rectifier K + channel KCNJ1.…”