CLCNKB – Bartter syndrome

Bartter syndrome is an autosomal recessive salt-wasting tubulopathy characterized by hypokalemia, metabolic alkalosis, polyuria, and secondary hyperreninemic hyperaldosteronism. The ClC-Kb chloride channel, encoded by CLCNKB, mediates basolateral Cl⁻ exit in the thick ascending limb of the loop of Henle and distal convoluted tubule. Loss-of-function variants in CLCNKB cause Bartter syndrome type III (Bartter syndrome).

Autosomal recessive inheritance is firmly established, with biallelic CLCNKB mutations in multiple unrelated families. Genotype analysis of five African American probands revealed homozygous deletion of CLCNKB, all presenting with failure to thrive and dehydration ([PMID:11445802]). In European and Asian cohorts, compound heterozygous and homozygous nonsense, frameshift, and splice variants have been described in at least 22 probands across 14 families, confirming robust segregation ([PMID:15875219]).

Case series report a diverse variant spectrum: complete gene deletions, nonsense (c.1830G>A (p.Trp610Ter)), missense (p.Ala204Thr founder allele in Spain), splice-site, and frameshift mutations. Recurrent alleles include c.610G>A (p.Ala204Thr) in Basque and Spanish patients ([PMID:15875219]), and c.1830G>A (p.Trp610Ter) in Chinese and Japanese cohorts ([PMID:15717167]). Prenatal presentations with polyhydramnios and premature birth (n=2 siblings) expand the phenotypic range ([PMID:11815871]).

Functional studies of >15 CLCNKB mutants demonstrate impaired plasma membrane expression and chloride conductance. Four variants (e.g., p.Gly246Arg, p.Gly424Glu) abolished current, while others reduced conductance by 30–60% without altering ion selectivity ([PMID:23703872]). Carboxyl-terminal truncations (e.g., W610X) disrupt barttin-dependent activation and surface trafficking, fully abrogating channel function ([PMID:26453302]). aminoglycoside-induced read-through of W610X partially rescues membrane localization in vitro ([PMID:23772144]).

No conflicting data have been reported to date. The concordance of genetic segregation with functional LoF, combined with consistent clinical phenotypes across diverse populations, supports a Strong ClinGen gene-disease validity classification.

Key take-home: CLCNKB genetic testing confirms diagnosis of Bartter syndrome type III, guides prenatal counseling, and may inform emerging read-through or chaperone therapies targeting specific LoF variants.

References

• The Journal of pediatrics • 2001 • Genotype/phenotype observations in African Americans with Bartter syndrome. PMID:11445802
• Pediatric nephrology • 2005 • A founder mutation in the CLCNKB gene causes Bartter syndrome type III in Spain. PMID:15875219
• Pediatric nephrology • 2005 • Renal cysts and nephrocalcinosis in a patient with Bartter syndrome type III. PMID:15717167
• Human mutation • 2013 • Novel CLCNKB mutations causing Bartter syndrome affect channel surface expression. PMID:23703872
• The Journal of biological chemistry • 2015 • Carboxyl-terminal Truncations of ClC-Kb Abolish Channel Activation by Barttin Via Modified Common Gating and Trafficking. PMID:26453302

Evidence Based Scoring (AI generated)