CLCNKB – Gitelman Syndrome

CLCNKB, encoding the basolateral ClC-Kb chloride channel, is established as an autosomal recessive cause of Gitelman syndrome (GS) characterized by hypokalaemic metabolic alkalosis, hypomagnesemia, and hypocalciuria. Patients harboring biallelic CLCNKB variants present with a spectrum ranging from classic Bartter-Gitelman overlap to a Gitelman-predominant phenotype, often with adult or atypical onset.

Inheritance is autosomal recessive, supported by homozygous or compound heterozygous mutations in multiple unrelated probands and an inbred family with four affected siblings exhibiting concordant tubular salt‐wasting phenotypes (3 additional relatives) (PMID:24711981). Case series include 8 probands with biallelic CLCNKB mutations across separate families, confirming AR segregation and clinical consistency (PMID:16391491; PMID:23345488).

The variant spectrum in GS includes missense, nonsense, splice‐site, and small indels. A founder missense variant, c.610G>A (p.Ala204Thr), recurs in Spanish cohorts and segregates in homozygous form, while other pathogenic missense changes such as p.Gly164Trp, p.Leu647Phe, and p.Trp610Ter are reported in diverse populations.

Functional studies demonstrate that truncating and missense CLCNKB mutants reduce channel surface expression and abolish or markedly diminish chloride conductance in Xenopus oocytes and mammalian cells. Partial loss-of-function variants display preserved gating but fail membrane trafficking, supporting haploinsufficiency as the mechanism (PMID:23703872; PMID:25810436).

No strong conflicting evidence has been reported regarding the GS phenotype; gain-of-function CLCNKB polymorphisms (e.g., p.Thr481Ser) have been linked to hypertension but do not overlap with GS cases.

In summary, CLCNKB biallelic loss-of-function variants cause an autosomal recessive Gitelman syndrome spectrum. Genetic testing of CLCNKB should be pursued in patients with unexplained hypokalaemic salt-wasting, particularly when SLC12A3 is negative. Early molecular diagnosis guides tailored electrolyte supplementation and NSAID therapy.

Key Take-Home: CLCNKB AR variants underlie a Gitelman syndrome spectrum with variable onset; genetic confirmation optimizes diagnosis and management in hypokalaemic tubulopathies.

References

• Hormone research • 2006 • A Spanish founder mutation in the chloride channel gene, CLCNKB, as a cause of atypical Bartter syndrome in adult age PMID:16391491
• BMJ case reports • 2013 • Gitelman or Bartter type 3 syndrome? A case of distal convoluted tubulopathy caused by CLCNKB gene mutation PMID:23345488
• SpringerPlus • 2014 • Mixed Bartter-Gitelman syndrome: an inbred family with a heterogeneous phenotype expression of a novel variant in the CLCNKB gene PMID:24711981
• Meta Gene • 2014 • A novel mutation of CLCNKB in a Japanese patient of Gitelman-like phenotype with diuretic insensitivity to thiazide administration PMID:25606418
• Endocrine Journal • 2014 • Bartter syndrome type 3 in an elderly complicated with adrenocorticotropin-deficiency PMID:24965226
• Kidney International • 2003 • Analysis of renal tubular electrolyte transporter genes in seven patients with hypokalemic metabolic alkalosis PMID:12911530
• Human Mutation • 2013 • Novel mutations of the chloride channel Kb gene in two Japanese patients clinically diagnosed as Bartter syndrome with hypocalciuria PMID:15531551
• PloS One • 2008 • A cytoplasmic domain mutation in ClC-Kb affects long-distance communication across the membrane PMID:18648499
• American Journal of Physiology • Renal Physiology • 2015 • ClC-K chloride channels: emerging pathophysiology of Bartter syndrome type 3 PMID:25810436
• Human Mutation • 2020 • Analysis of CLCNKB mutations at dimer-interface, calcium-binding site, and pore reveals a variety of functional alterations in ClC-Kb channel leading to Bartter syndrome PMID:31803959

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