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CLCN5
Cl-/H+ antiporter 5
The CLCN5 gene provides instructions for making a protein that plays a vital role in kidney function, specifically in reabsorbing proteins and other substances within the renal tubules. The CLCN5 gene encodes a protein that acts as a chloride/hydrogen antiporter, essential for maintaining the proper acidity levels within kidney cells.
CLCN5 is located on the short (p) arm of chromosome X, at band Xp11.23. Arm ratio per GRCh38 - banding schematic.
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Overview
The CLCN5 gene, also known as Cl-/H+ antiporter 5, is located on the X chromosome and is fundamental for normal kidney function. It produces a protein that is particularly active in the proximal tubules of the kidneys, which are responsible for reabsorbing essential proteins and other molecules back into the bloodstream.
When the CLCN5 protein does not function correctly, it can lead to conditions such as Dent disease, characterised by impaired kidney reabsorption and significant protein loss in the urine.
What the gene does
The CLCN5 gene provides the blueprint for a protein that transports charged molecules, specifically exchanging negatively charged chloride ions for positively charged hydrogen ions, across cell membranes. This protein is predominantly found in the proximal tubules of the kidneys, where it facilitates the reabsorption of proteins and other vital substances.
Within the cells of the proximal tubules, the CLCN5 protein is located in specialised compartments called endosomes. These endosomes are crucial for reabsorbing proteins and transporting various molecules within the cell, a process known as endocytosis. By managing the movement of hydrogen and chloride ions, the CLCN5 protein helps maintain the precise acidic pH environment within endosomes that is necessary for proper cellular function in the kidneys.
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Chromosome location
The CLCN5 gene is situated on the short arm of the X chromosome at position Xp11.23. As an X-linked gene, conditions associated with CLCN5 typically follow an X-linked inheritance pattern.
Protein structure
The CLCN5 protein is composed of 816 amino acids. It features a Disordered region at its N-terminus (amino acids 1-26). Key functional components include three Selectivity filter parts (Motif) located at amino acids 237-241, 279-283, and 523-527, which are critical for ion selectivity. The protein also contains two CBS domains: CBS 1 (amino acids 656-720) and CBS 2 (amino acids 752-812), which are thought to play a role in regulating channel activity.
Key variants
Genetic variations within the CLCN5 gene can alter the structure and function of the encoded protein. These changes may impede the protein's ability to properly transport ions and maintain pH balance in kidney cells, leading to impaired renal reabsorption. Such variations are often associated with inherited kidney disorders.
Sample of pathogenic variants
10 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.1014+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | X-linked recessive nephrolithiasis with renal failure |
c.1249C>T | p.Arg417Ter | Pathogenic | ★★☆☆ | Dent disease type 1 |
c.1275T>G | p.Tyr425Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Hypophosphatemic rickets, X-linked recessive |
c.1329dup | p.Asn444fs | Pathogenic | ★★☆☆ | Dent disease type 1 |
c.1386_1387del | p.Cys462fs | Pathogenic | ★★☆☆ | Dent disease type 1 |
c.1609C>T | p.Arg537Ter | Pathogenic | ★★☆☆ | CLCN5-related disorder |
c.2362C>T | p.Arg788Ter | Pathogenic | ★★☆☆ | Proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis |
c.292C>T | p.Arg98Ter | Pathogenic/Likely pathogenic | ★★☆☆ | CLCN5-related disorder |
c.328del | p.Ser110fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.845del | p.Gly282fs | Pathogenic | ★★☆☆ | not provided |
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 CLCN5 gene are primarily linked to Dent disease, specifically Dent disease 1. This is an X-linked condition predominantly affecting males, characterised by chronic kidney disease, which can progress to kidney failure, along with other associated health issues. The clinical presentation can vary depending on the specific genetic change.
Inheritance pattern
Conditions caused by pathogenic CLCN5 variants typically follow x-linked inheritance.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
UK clinical status
The CLCN5 gene is recognised within the NHS Genomic Medicine Service due to its association with several kidney-related conditions. It is listed on multiple Green RAG status panels in PanelApp, indicating strong evidence for its involvement in these conditions. These include panels for Cystic kidney disease, Nephrocalcinosis or nephrolithiasis, Proteinuric renal disease, Renal tubulopathies, Skeletal dysplasia, and Unexplained kidney failure in young people.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the CLCN5 gene?
The CLCN5 gene provides instructions for a protein that acts as a chloride/hydrogen antiporter. This protein is essential for maintaining the proper acidic environment within endosomes of kidney cells, which is crucial for reabsorbing proteins and other important substances.
Which condition is most commonly associated with CLCN5 gene variants?
Variants in the CLCN5 gene are most commonly associated with Dent disease, particularly Dent disease 1. This inherited disorder primarily affects the kidneys, leading to symptoms such as excessive protein in the urine and, in some cases, kidney failure.
Why is CLCN5 considered an X-linked gene?
CLCN5 is located on the X chromosome. Conditions caused by variants in this gene follow an X-linked inheritance pattern, meaning they predominantly affect males, who have only one X chromosome, more severely than females.
References
- Lourdel S, Grand T, Burgos J. ClC-5 mutations associated with Dent's disease: a major role of the dimer interface. Pflugers Archiv : European journal of physiology. 2012. PMID: 22083641
- Claverie-Martín F, Ramos-Trujillo E, García-Nieto V. Dent's disease: clinical features and molecular basis. Pediatric nephrology (Berlin, Germany). 2011. PMID: 20936522
- Wellhauser L, D'Antonio C, Bear CE. ClC transporters: discoveries and challenges in defining the mechanisms underlying function and regulation of ClC-5. Pflugers Archiv : European journal of physiology. 2010. PMID: 20049483
- Christensen EI, Devuyst O, Dom G. Loss of chloride channel ClC-5 impairs endocytosis by defective trafficking of megalin and cubilin in kidney proximal tubules. Proceedings of the National Academy of Sciences of the United States of America. 2003. PMID: 12815097
- Cox JP, Yamamoto K, Christie PT. Renal chloride channel, CLCN5, mutations in Dent's disease. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 1999. PMID: 10469281
- Devuyst O, Christie PT, Courtoy PJ. Intra-renal and subcellular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent's disease. Human molecular genetics. 1999. PMID: 9931332
- Fisher SE, van Bakel I, Lloyd SE. Cloning and characterization of CLCN5, the human kidney chloride channel gene implicated in Dent disease (an X-linked hereditary nephrolithiasis). Genomics. 1995. PMID: 8575751