The SLC12A3 gene provides instructions for making a protein known as NCC. This protein is a sodium chloride co-transporter, which means that it moves charged atoms (ions) of sodium (Na+) and chlorine (Cl-) across cell membranes.
The NCC protein is essential for normal kidney function. It is part of the mechanism by which kidneys reabsorb salt (sodium chloride or NaCl) from the urine back into the bloodstream. The retention of salt affects the body's fluid levels and helps maintain blood pressure.
Health Conditions Related to Genetic Changes
More than 140 mutations in the SLC12A3 gene have been identified in people with Gitelman syndrome. Most of these mutations change single protein building blocks (amino acids) in the NCC co-transporter protein. These mutations prevent the protein from reaching the cell membrane or alter the protein's ability to transport sodium and chloride ions. Other mutations in the SLC12A3 gene insert or delete genetic material or lead to the production of an abnormally short, nonfunctional version of the NCC protein.
Mutations in the SLC12A3 gene impair the kidneys' ability to reabsorb salt, leading to the loss of excess salt in the urine (salt wasting). Abnormalities of salt transport also affect the reabsorption of other ions, including ions of potassium, magnesium, and calcium. The resulting imbalance of ions in the body underlies the major features of Gitelman syndrome.More About This Health Condition
Some research suggests that normal variants (polymorphisms) in the SLC12A3 gene may help explain differences in blood pressure between people. Certain rare polymorphisms also appear to protect against high blood pressure (hypertension). Changes in the SLC12A3 gene may affect blood pressure by altering the kidneys' ability to reabsorb salt into the bloodstream. However, some studies have not found any association between variants in the SLC12A3 gene and blood pressure.
Other Names for This Gene
- Na-Cl symporter
- NaCl electroneutral thiazide-sensitive cotransporter
- solute carrier family 12 (sodium/chloride transporter), member 3
- solute carrier family 12 (sodium/chloride transporters), member 3
- thiazide-sensitive Na-Cl cotransporter
- thiazide-sensitive sodium-chloride cotransporter
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
- Aoi N, Nakayama T, Sato N, Kosuge K, Haketa A, Sato M, Soma M. Case-control study of the role of the Gitelman's syndrome gene in essential hypertension. Endocr J. 2008 May;55(2):305-10. doi: 10.1507/endocrj.k07e-021. Epub 2008 Mar 25. Citation on PubMed
- Cruz DN, Simon DB, Nelson-Williams C, Farhi A, Finberg K, Burleson L, Gill JR, Lifton RP. Mutations in the Na-Cl cotransporter reduce blood pressure in humans. Hypertension. 2001 Jun;37(6):1458-64. doi: 10.1161/01.hyp.37.6.1458. Citation on PubMed
- De Jong JC, Van Der Vliet WA, Van Den Heuvel LP, Willems PH, Knoers NV, Bindels RJ. Functional expression of mutations in the human NaCl cotransporter: evidence for impaired routing mechanisms in Gitelman's syndrome. J Am Soc Nephrol. 2002 Jun;13(6):1442-8. doi: 10.1097/01.asn.0000017904.77985.03. Citation on PubMed
- Ji W, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State MW, Levy D, Lifton RP. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet. 2008 May;40(5):592-599. doi: 10.1038/ng.118. Epub 2008 Apr 6. Citation on PubMed or Free article on PubMed Central
- Lemmink HH, Knoers NV, Karolyi L, van Dijk H, Niaudet P, Antignac C, Guay-Woodford LM, Goodyer PR, Carel JC, Hermes A, Seyberth HW, Monnens LA, van den Heuvel LP. Novel mutations in the thiazide-sensitive NaCl cotransporter gene in patients with Gitelman syndrome with predominant localization to the C-terminal domain. Kidney Int. 1998 Sep;54(3):720-30. doi: 10.1046/j.1523-1755.1998.00070.x. Citation on PubMed
- Lo YF, Nozu K, Iijima K, Morishita T, Huang CC, Yang SS, Sytwu HK, Fang YW, Tseng MH, Lin SH. Recurrent deep intronic mutations in the SLC12A3 gene responsible for Gitelman's syndrome. Clin J Am Soc Nephrol. 2011 Mar;6(3):630-9. doi: 10.2215/CJN.06730810. Epub 2010 Nov 4. Citation on PubMed or Free article on PubMed Central
- Mastroianni N, De Fusco M, Zollo M, Arrigo G, Zuffardi O, Bettinelli A, Ballabio A, Casari G. Molecular cloning, expression pattern, and chromosomal localization of the human Na-Cl thiazide-sensitive cotransporter (SLC12A3). Genomics. 1996 Aug 1;35(3):486-93. doi: 10.1006/geno.1996.0388. Citation on PubMed
- Riveira-Munoz E, Chang Q, Godefroid N, Hoenderop JG, Bindels RJ, Dahan K, Devuyst O; Belgian Network for Study of Gitelman Syndrome. Transcriptional and functional analyses of SLC12A3 mutations: new clues for the pathogenesis of Gitelman syndrome. J Am Soc Nephrol. 2007 Apr;18(4):1271-83. doi: 10.1681/ASN.2006101095. Epub 2007 Feb 28. Citation on PubMed
- Sabath E, Meade P, Berkman J, de los Heros P, Moreno E, Bobadilla NA, Vazquez N, Ellison DH, Gamba G. Pathophysiology of functional mutations of the thiazide-sensitive Na-Cl cotransporter in Gitelman disease. Am J Physiol Renal Physiol. 2004 Aug;287(2):F195-203. doi: 10.1152/ajprenal.00044.2004. Epub 2004 Apr 6. Citation on PubMed
- Simon DB, Nelson-Williams C, Bia MJ, Ellison D, Karet FE, Molina AM, Vaara I, Iwata F, Cushner HM, Koolen M, Gainza FJ, Gitleman HJ, Lifton RP. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet. 1996 Jan;12(1):24-30. doi: 10.1038/ng0196-24. Citation on PubMed
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