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CLCNKB
chloride voltage-gated channel Kb
The CLCNKB gene encodes a chloride channel, ClC-Kb, which is predominantly expressed in the kidneys and plays a vital role in salt reabsorption and maintaining fluid balance. The CLCNKB gene provides the blueprint for the ClC-Kb chloride channel, a crucial protein for kidney function.
CLCNKB is located on the short (p) arm of chromosome 1, at band 1p36.13. Arm ratio per GRCh38 - banding schematic.
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Overview
The CLCNKB gene is part of the CLC family, which are genes responsible for producing chloride channels. These channels facilitate the movement of negatively charged chlorine atoms (chloride ions) across cellular membranes, a process fundamental to generating and transmitting electrical signals within cells. The protein encoded by CLCNKB, known as ClC-Kb, is primarily located in the kidneys.
Within the kidneys, ClC-Kb works alongside other proteins to regulate ion movement in and out of kidney cells. This regulation is key to the kidneys' ability to reabsorb salt (sodium chloride) from urine back into the bloodstream, a mechanism that influences the body's fluid levels and helps regulate blood pressure.
What the gene does
The CLCNKB gene provides instructions for synthesising the ClC-Kb chloride channel. This channel is crucial for the transport of chloride ions, which are negatively charged chlorine atoms, across cell membranes. In the kidneys, ClC-Kb channels are integral to the process of salt reabsorption, specifically drawing sodium chloride from the forming urine back into the circulatory system. This reabsorption is essential for maintaining the body's fluid balance and supporting healthy blood pressure levels.
Beyond the kidneys, ClC-Kb channels are also found in the inner ear, where they contribute to the mechanisms underlying normal hearing. The precise regulation of chloride ion flow by ClC-Kb is therefore vital for both renal physiological processes and auditory function.
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Chromosome location
The CLCNKB gene is situated on the short arm of chromosome 1, at position 1p36.13. This specific genomic location provides the blueprint for the ClC-Kb protein, which consists of 687 amino acids.
Protein structure
The ClC-Kb protein, encoded by the CLCNKB gene, is composed of 687 amino acids. It includes two key CBS (cystathionine beta-synthase) domains. CBS 1 spans amino acid residues 551 to 609, while CBS 2 is located from amino acids 626 to 684. These domains are known to be involved in regulating the activity of ion channels.
Key variants
Variations within the CLCNKB gene can alter the structure or function of the ClC-Kb chloride channel. These genetic changes can range from single nucleotide alterations to larger deletions affecting the entire gene. Depending on their nature and location, such variations can lead to impaired salt reabsorption in the kidneys, impacting fluid and electrolyte balance in the body.
Sample of pathogenic variants
9 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.18dup | p.Leu7fs | Pathogenic | ★★☆☆ | Bartter disease type 3 |
c.36del | p.Asn14fs | Pathogenic/Likely pathogenic | ★★☆☆ | Bartter disease type 4B |
c.73del | p.Cys25fs | Pathogenic | ★★☆☆ | Bartter disease type 3 |
g.(?_16370276)_(16372182_16373029)del | - | Pathogenic | ★☆☆☆ | Bartter syndrome |
g.(?_16370276)_(16377096_16377369)del | - | Pathogenic | ★☆☆☆ | Bartter syndrome |
g.(?_16370276)_(16383804_?)del | - | Pathogenic | ★☆☆☆ | Bartter syndrome |
c.(?_-1)_(*1_?)del | - | Pathogenic | ★☆☆☆ | Bartter disease type 3 |
GRCh37/hg19 1p36.13(chr1:16370960-16383841) | - | Pathogenic | - | Bartter disease type 3 |
g.(?_16043782)_(16057326_?)del | - | Pathogenic | - | Bartter disease type 3 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the CLCNKB gene are primarily associated with Bartter syndrome, an inherited kidney disorder. Specifically, they are linked to Bartter syndrome type III, which is often referred to as classical Bartter syndrome and typically manifests during childhood with a generally milder presentation than other forms. Mutations in CLCNKB can also be a rare cause of Gitelman syndrome, another condition affecting renal salt reabsorption.
Inheritance pattern
Conditions caused by pathogenic CLCNKB variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The CLCNKB gene is recognised in the UK's NHS Genomic Medicine Service, being listed on PanelApp. It is included in panels for inherited conditions such as Developmental Disorders (DDG2P), Foetal anomalies (R21), Nephrocalcinosis or nephrolithiasis (R256), and Renal tubulopathies (R198), indicating its clinical significance within these areas.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the CLCNKB gene?
The CLCNKB gene provides instructions for creating the ClC-Kb chloride channel, which is crucial for transporting chloride ions. This channel is predominantly found in the kidneys, where it plays a key role in reabsorbing salt to maintain fluid balance and blood pressure.
Which conditions are associated with variants in the CLCNKB gene?
Variants in the CLCNKB gene are primarily associated with Bartter syndrome, particularly type III. In rare instances, they can also cause Gitelman syndrome. Both conditions involve impaired salt reabsorption in the kidneys.
How does the CLCNKB gene affect kidney function?
The ClC-Kb channel encoded by CLCNKB helps the kidneys reabsorb salt (sodium chloride) from the urine back into the bloodstream. This process is vital for regulating the body's fluid levels and maintaining normal blood pressure.
References
- Enríquez R, Adam V, Sirvent AE. Gitelman syndrome due to p.A204T mutation in CLCNKB gene. International urology and nephrology. 2010. PMID: 20931281
- Krämer BK, Bergler T, Stoelcker B. Mechanisms of Disease: the kidney-specific chloride channels ClCKA and ClCKB, the Barttin subunit, and their clinical relevance. Nature clinical practice. Nephrology. 2008. PMID: 18094726
- Nozu K, Inagaki T, Fu XJ. Molecular analysis of digenic inheritance in Bartter syndrome with sensorineural deafness. Journal of medical genetics. 2008. PMID: 18310267
- Jeck N, Waldegger P, Doroszewicz J. A common sequence variation of the CLCNKB gene strongly activates ClC-Kb chloride channel activity. Kidney international. 2004. PMID: 14675050
- Schlingmann KP, Konrad M, Jeck N. Salt wasting and deafness resulting from mutations in two chloride channels. The New England journal of medicine. 2004. PMID: 15044642
- Jeck N, Waldegger S, Lampert A. Activating mutation of the renal epithelial chloride channel ClC-Kb predisposing to hypertension. Hypertension (Dallas, Tex. : 1979). 2004. PMID: 15148291
- Konrad M, Vollmer M, Lemmink HH. Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome. Journal of the American Society of Nephrology : JASN. 2000. PMID: 10906158
- Jeck N, Konrad M, Peters M. Mutations in the chloride channel gene, CLCNKB, leading to a mixed Bartter-Gitelman phenotype. Pediatric research. 2000. PMID: 11102542
- Simon DB, Bindra RS, Mansfield TA. Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III. Nature genetics. 1997. PMID: 9326936
- Kieferle S, Fong P, Bens M. Two highly homologous members of the ClC chloride channel family in both rat and human kidney. Proceedings of the National Academy of Sciences of the United States of America. 1994. PMID: 8041726