Bartters Syndrome Type Iii A Disease of CLCKb

Bartter's syndrome is an autosomal recessive disorder characterised by severe salt-wasting, that may lead to a marked depletion of the extracellular volume, low blood pressure, hypokalaemia, hypercalciuria and alkalosis. The clinical features are described more fully in Chapter 8. Mutations in three different genes are known to produce Bartter's syndrome: the NaK2Cl cotransporter (SCL12A1, Bartter's syndrome type I), the inwardly-rectifying K+ channel Kir1.1 (KCNJ1; Bartter's syndrome type II) and the voltage-gated Cl" channel CLC-Kb (CLCNKB; Bartter's syndrome type III). In contrast to patients with Bartter's syndrome types I and II, patients with mutations in CLCNKB do not suffer from nephrocalcinosis, despite elevation of the urinary calcium concentration.

Mutations in CLCNKB associated with Bartter's syndrome type III have been identified in seventeen kindreds of diverse ethnic background (Simon et al, 1997b). They include five missense mutations, one nonsense mutation and one splice-site mutation (Fig. 10.8). In the other ten kindreds either the entire CLCNKB gene, or a substantial portion of it, was deleted. Some of these deletions appear to have arisen by unequal crossing over between CLCNKB and the related Cl" channel gene CLCNKA. These genes lie side by side on chromosome 1, in the same transcriptional orientation and are separated by 11 kb. They have an identical genomic organization (both contain 19 introns) and share 94% DNA sequence identity within the exons, suggesting that they were produced by duplication of a single ancestral gene. Crossing-over between the exons of CLCNKA and CLCNKB in some kindreds has resulted in chimeric genes consisting of some parts of each gene, with the CLCNKA portion 5' to the CLCNKB sequence. All the deletions and mutations identified in Bartter's syndrome type III kindreds are presumed to result in a decreased Cl" conductance.

Figure 10.9 explains why a reduction in CLC-Kb results in Bartter's syndrome. The renal tubules reabsorb more than 99% of the fluid filtered by the glomeruli, which amounts to around 180 litres each day. Most salt reabsorp-

Clcnkb Mutations

FIGURE 10.8 Cl~ CHANNEL MUTATIONS ASSOCIATED WITH BARTTER'S SYNDROME TYPE III

Predicted topology of CLC-Kb with the mutations causing Bartter's syndrome type III indicated.

FIGURE 10.8 Cl~ CHANNEL MUTATIONS ASSOCIATED WITH BARTTER'S SYNDROME TYPE III

Predicted topology of CLC-Kb with the mutations causing Bartter's syndrome type III indicated.

Tubi lum

Tubi lum

Thick Ascending Loop Henle

Basolateral

Apical

FIGURE 10.9 SALT TRANSPORT IN THE THICK ASCENDING LOOP OF HENLE

The apical membrane of the cells of the thick ascending loop of Henle contains a NaK2Cl cotransporter which mediates the uptake of one Na+, one K+ and two Cl" ions. Energy for this process is provided by the Na+ gradient generated by the activity of the Na/K-ATPase in the basolateral membrane. The Cl" ions translocated by the NaK2Cl cotransporter leave the cell via CLC-Kb channels in the basolateral membrane and in their absence the activity of the NaK2Cl cotransporter will be inhibited, leading to loss of Na+, Cl" and K+ in the urine.

Basolateral

Apical

FIGURE 10.9 SALT TRANSPORT IN THE THICK ASCENDING LOOP OF HENLE

The apical membrane of the cells of the thick ascending loop of Henle contains a NaK2Cl cotransporter which mediates the uptake of one Na+, one K+ and two Cl" ions. Energy for this process is provided by the Na+ gradient generated by the activity of the Na/K-ATPase in the basolateral membrane. The Cl" ions translocated by the NaK2Cl cotransporter leave the cell via CLC-Kb channels in the basolateral membrane and in their absence the activity of the NaK2Cl cotransporter will be inhibited, leading to loss of Na+, Cl" and K+ in the urine.

tion occurs constitutively within the proximal tubule, but significant reabsorption also takes place across the cells of the thick ascending limb of the loop of Henle. The latter is essential for the formation of a concentrated urine. Na+, K+ and Cl" enter the cell via the NaK2Cl cotransporter in the apical membrane as a consequence of the electrochemical gradient for Na+ that is produced by the activity of the basolateral Na/K-ATPase. K+ ions are recycled across the apical membrane via the inwardly rectifying K+ channel, Kirl.1 (see Chapter 8), while Cl" exits to the plasma through Cl" channels in the basolateral membrane. The facts that CLC-Kb is expressed in the loop of Henle and that mutations in this protein produce Bartter's syndrome suggest that CLC-Kb comprises the basolateral Cl" channel. Loss of this channel may be expected to lead to an intracellular accumulation of Cl", which will reduce the activity of the NaK2Cl cotransporter and lead to the loss of Na+, Cl" and K+ in the urine. The blood concentrations of these ions will therefore be lowered. There will also be an associated diuresis, which accounts for the hypovolaemia and hypotension characteristic of Bartter's syndrome. Patients with Bartter's syndrome type III exhibit marked variability in the severity of the clinical features. It is not yet known whether this is linked to variation in the level of Cl" conductance produced by the different CLCNKB mutations.

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