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Normal Function
The CLCN5 gene provides instructions for making a protein that transports charged molecules (ions) across cell membranes. Specifically, the CLCN5 protein exchanges negatively charged chloride ions for positively charged hydrogen ions.
The CLCN5 protein is found primarily in structures called proximal tubules in the kidneys. The proximal tubules help to reabsorb protein and other important substances back into the bloodstream. Substances that are not reabsorbed by the kidneys are released into the urine. Thus, the CLCN5 protein helps prevent protein loss in the urine (proteinuria).
Within proximal tubular cells, the CLCN5 protein is found in specialized compartments called endosomes. Endosomes at the proximal tubular cell surface are involved in the reabsorption of proteins. They also help transport proteins and other molecules to their proper locations within the cell. The process of transporting proteins from the outer cell membrane to the inside of the cell is called endocytosis.
By transporting hydrogen ions into endosomes and chloride ions out, the CLCN5 protein helps endosomes maintain the proper acidity level (pH). Endosomal pH levels must be acidic for the proximal tubular cells to function properly.
Health Conditions Related to Genetic Changes
Dent disease
Changes in the CLCN5 gene can cause a type of Dent disease called Dent disease 1. Genetic changes that cause disease are called pathogenic variants. Dent disease 1 occurs almost exclusively in males. This condition is characterized by chronic kidney disease that can lead to kidney failure and other health problems. Many of the pathogenic variants that are associated with Dent disease 1 cause cells to make a version of the protein that does not function properly. This impairs the regulation of endosomal pH and disrupts endocytosis and protein reabsorption in the proximal tubules. As a result, proteins and nutrients that should be reabsorbed into the bloodstream are released in the urine. This can contribute to the bone defects, kidney stones, and related health problems seen in people with Dent disease 1.
More About This Health Condition
Other Names for This Gene
- ClC-5
- CLC5
- Dent disease
- DENTS
- hCIC-K2
- XLRH
- XRN
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Christensen EI, Devuyst O, Dom G, Nielsen R, Van der Smissen P, Verroust P, Leruth M, Guggino WB, Courtoy PJ. Loss of chloride channel ClC-5 impairs endocytosis by defective trafficking of megalin and cubilin in kidney proximal tubules. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8472-7. doi: 10.1073/pnas.1432873100. Epub 2003 Jun 18. Citation on PubMed or Free article on PubMed Central
- Claverie-Martin F, Ramos-Trujillo E, Garcia-Nieto V. Dent's disease: clinical features and molecular basis. Pediatr Nephrol. 2011 May;26(5):693-704. doi: 10.1007/s00467-010-1657-0. Epub 2010 Oct 10. Citation on PubMed
- Cox JP, Yamamoto K, Christie PT, Wooding C, Feest T, Flinter FA, Goodyer PR, Leumann E, Neuhaus T, Reid C, Williams PF, Wrong O, Thakker RV. Renal chloride channel, CLCN5, mutations in Dent's disease. J Bone Miner Res. 1999 Sep;14(9):1536-42. doi: 10.1359/jbmr.1999.14.9.1536. Citation on PubMed
- Devuyst O, Christie PT, Courtoy PJ, Beauwens R, Thakker RV. Intra-renal and subcellular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent's disease. Hum Mol Genet. 1999 Feb;8(2):247-57. doi: 10.1093/hmg/8.2.247. Citation on PubMed
- Ehlayel AM, Copelovitch L. Update on Dent Disease. Pediatr Clin North Am. 2019 Feb;66(1):169-178. doi: 10.1016/j.pcl.2018.09.003. Citation on PubMed
- Fisher SE, van Bakel I, Lloyd SE, Pearce SH, Thakker RV, Craig IW. Cloning and characterization of CLCN5, the human kidney chloride channel gene implicated in Dent disease (an X-linked hereditary nephrolithiasis). Genomics. 1995 Oct 10;29(3):598-606. doi: 10.1006/geno.1995.9960. Citation on PubMed
- Gianesello L, Del Prete D, Ceol M, Priante G, Calo LA, Anglani F. From protein uptake to Dent disease: An overview of the CLCN5 gene. Gene. 2020 Jul 15;747:144662. doi: 10.1016/j.gene.2020.144662. Epub 2020 Apr 11. Citation on PubMed
- Jin YY, Huang LM, Quan XF, Mao JH. Dent disease: classification, heterogeneity and diagnosis. World J Pediatr. 2021 Feb;17(1):52-57. doi: 10.1007/s12519-020-00357-1. Epub 2020 Apr 4. Citation on PubMed
- Lieske JC, Milliner DS, Beara-Lasic L, Harris P, Cogal A, Abrash E. Dent Disease. 2012 Aug 9 [updated 2017 Dec 14]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK99494/ Citation on PubMed
- Lourdel S, Grand T, Burgos J, Gonzalez W, Sepulveda FV, Teulon J. ClC-5 mutations associated with Dent's disease: a major role of the dimer interface. Pflugers Arch. 2012 Feb;463(2):247-56. doi: 10.1007/s00424-011-1052-0. Epub 2011 Nov 15. Citation on PubMed
- Wellhauser L, D'Antonio C, Bear CE. ClC transporters: discoveries and challenges in defining the mechanisms underlying function and regulation of ClC-5. Pflugers Arch. 2010 Jul;460(2):543-57. doi: 10.1007/s00424-009-0769-5. Epub 2010 Jan 5. Citation on PubMed
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