CLCNKB – Bartter disease type 3

Classic Bartter disease type 3 is an autosomal recessive salt-losing tubulopathy caused by biallelic inactivating variants in the CLCNKB gene, which encodes the basolateral ClC-Kb chloride channel expressed in the renal thick ascending limb and distal convoluted tubule. Patients present with hypokalemic metabolic alkalosis, secondary hyperreninism and hyperaldosteronism, renal salt wasting, and normal to low blood pressure.

Genetic studies have identified biallelic CLCNKB mutations in over 30 unrelated probands from 30 families worldwide, supporting a consistent recessive inheritance ([PMID:10906158]). Compound heterozygous missense variants (e.g., A61D/V149E) and small deletions have been observed segregating in affected sib-pairs ([PMID:16306206]). The spectrum includes missense, nonsense, frameshift, essential splice, and large multi-exon deletions, with variable age at onset ranging from neonatal volume depletion to asymptomatic adolescence.

One representative disease-causing allele is c.446T>A (p.Val149Glu), a missense change that abolishes chloride conductance in heterologous systems and has been reported in multiple ethnic groups overlapping with classic Bartter phenotypes.

Functional assays in Xenopus oocytes and mammalian cells demonstrate that LoF CLCNKB variants reduce or abolish ClC-Kb current, impair proper membrane trafficking, and destabilize channel gating, consistent with haploinsufficiency as the primary pathogenic mechanism ([PMID:25810436]). Rescue experiments with accessory subunit barttin partially restore channel expression but not full function, highlighting the critical role of ClC-Kb structural integrity.

No robust evidence disputes the CLCNKB–Bartter type 3 association; genotype–phenotype correlations show that complete loss-of-function alleles present earlier and with more severe electrolyte disturbances, whereas residual conductance correlates with milder courses.

In summary, CLCNKB is definitively established as the causative gene for Bartter disease type 3. Genetic testing for CLCNKB variants is essential for accurate diagnosis, family counseling, and guiding potential future therapies targeting channel rescue. Key Take-home: Recessive CLCNKB LoF variants reliably predict classic Bartter type 3 and inform clinical management.

References

• Journal of the American Society of Nephrology • 2000 • Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome PMID:10906158
• Pediatric Research • 2005 • Simultaneous mutations in the CLCNKB and SLC12A3 genes in two siblings with phenotypic heterogeneity in classic Bartter syndrome PMID:16306206
• American Journal of Physiology Renal Physiology • 2015 • ClC-K chloride channels: emerging pathophysiology of Bartter syndrome type 3 PMID:25810436

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