Sodium-chloride symporter
| SLC12A3 | |||
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| Sources:Amigo / QuickGO | |||
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| Location (UCSC) | Chr 16: 56.87 – 56.92 Mb | Chr 8: 95.06 – 95.09 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
The sodium-chloride symporter (also known as Na+-Cl− cotransporter, NCC or NCCT, or as the thiazide-sensitive Na+-Cl− cotransporter or TSC) is a
A loss of NCC function causes Gitelman syndrome, an autosomic recessive disease characterized by salt wasting and low blood pressure, hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria.[6] Over a hundred different mutations in the NCC gene have been identified.
Molecular biology
The sodium-chloride symporter or NCC is a member of the SLC12 cotransporter family of electroneutral cation-coupled chloride cotransporter, along with the
Function
Because NCC is located at the
As NCC has to be at the plasma membrane to function, its activity can be regulated by increasing or decreasing the amount of protein at the plasma membrane. Some NCC modulators, such as the WNK3 and WNK4 kinases may regulate the amount of NCC at the cell surface by inducing the insertion or removal, respectively, of the protein from the plasma membrane.[8][9]
Furthermore, many residues of NCC can be phosphorylated or dephosphorylated to activate or inhibit NCC uptake of Na+ and Cl−. Other NCC modulators, including intracellular chloride depletion,
Pathology
Gitelman syndrome
A loss of NCC function is associated with Gitelman syndrome, an autosomic recessive disease characterized by salt wasting and low blood pressure, hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria.[6]
Over a hundred different mutations in the NCC gene have been described as causing Gitelman syndrome, including nonsense, frameshift, splice site and missense mutations. Two different types of mutations exist within the group of missense mutations causing loss of NCC function. Type I mutations cause a complete loss of NCC function, in which the synthesized protein is not properly glycosylated. NCC protein harboring type I mutations is retained in the endoplasmic reticulum and cannot be trafficked to the cell surface.[13] Type II mutations cause a partial loss of NCC function in which the cotransporter is trafficked to the cell surface but has an impaired insertion in the plasma membrane. NCC harboring type II mutations have normal kinetic properties but are present in lower amounts at the cell surface, resulting in a decreased uptake of sodium and chloride.[14] NCC harboring type II mutations is still under control of its modulators and can still increase or decrease its activity in response to stimuli, whereas type I mutations cause a complete loss of function and regulation of the cotransporter.[15] However, in some patients with Gitelman's syndrome, no mutations in the NCC gene have been found despite extensive genetic work-up.
Hypertension and blood pressure
NCC has also been implicated to play a role in control of
Furthermore, heterozygous
Pseudohypoaldosteronism type II
Type II pseudohypoaldosteronism (PHA2), also known as Gordon's syndrome, is an autosomal dominant disease in which there is an increase in NCC activity leading to short stature, increased blood pressure, increased serum K+ levels, increased urinary calcium excretion and hyperchloremic metabolic acidosis. However, PHA2 is not caused by mutations within the NCC gene, but by mutations in NCC regulators WNK1 and WNK4. Patients respond well to treatment with thiazide-type diuretics.
See also
- Nephron
- Distal convoluted tubule
- Electrolytes, such as sodium and chloride
- Cotransporter, including symporter
- Blood pressure
- thiazides
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000070915 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000031766 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 8812482.
- ^ PMID 18667063.
- PMID 19474192.
- PMID 16275913.
- PMID 19875813.
- PMID 16887815.
- PMID 20720527.
- PMID 20445498.
- PMID 12039972.
- PMID 15068971.
- ^ S2CID 205630437.
- PMID 18391953.
- PMID 17981812.
Further reading
- Kamdem LK, Hamilton L, Cheng C, et al. (2008). "Genetic predictors of glucocorticoid-induced hypertension in children with acute lymphoblastic leukemia". Pharmacogenet. Genomics. 18 (6): 507–14. S2CID 1251203.
- Coto E, Arriba G, GarcÃa-Castro M, et al. (2009). "Clinical and analytical findings in Gitelman's syndrome associated with homozygosity for the c.1925 G>A SLC12A3 mutation". Am. J. Nephrol. 30 (3): 218–21. S2CID 41050205.
- Yasujima M, Tsutaya S (2009). "[Mutational analysis of a thiazide-sensitive Na-Cl cotransporter (SLC12A3) gene in a Japanese population—the Iwaki Health Promotion Project]". Rinsho Byori. 57 (4): 391–6. PMID 19489442.
- Shao L, Liu L, Miao Z, et al. (2008). "A novel SLC12A3 splicing mutation skipping of two exons and preliminary screening for alternative splice variants in human kidney". Am. J. Nephrol. 28 (6): 900–7. S2CID 19321638.
- van Rijn-Bikker PC, Mairuhu G, van Montfrans GA, et al. (2009). "Genetic factors are relevant and independent determinants of antihypertensive drug effects in a multiracial population". Am. J. Hypertens. 22 (12): 1295–302. PMID 19779464.
- Shao L, Ren H, Wang W, et al. (2008). "Novel SLC12A3 mutations in Chinese patients with Gitelman's syndrome". Nephron Physiol. 108 (3): 29–36. S2CID 25283004.
- Ji W, Foo JN, O'Roak BJ, et al. (2008). "Rare independent mutations in renal salt handling genes contribute to blood pressure variation". Nat. Genet. 40 (5): 592–9. PMID 18391953.
- Riveira-Munoz E, Devuyst O, Belge H, et al. (2008). "Evaluating PVALB as a candidate gene for SLC12A3-negative cases of Gitelman's syndrome". Nephrol. Dial. Transplant. 23 (10): 3120–5. PMID 18469313.
- Zhou B, Zhuang J, Gu D, et al. (2010). "WNK4 enhances the degradation of NCC through a sortilin-mediated lysosomal pathway". J. Am. Soc. Nephrol. 21 (1): 82–92. PMID 19875813.
- Hsu YJ, Yang SS, Chu NF, et al. (2009). "Heterozygous mutations of the sodium chloride cotransporter in Chinese children: prevalence and association with blood pressure". Nephrol. Dial. Transplant. 24 (4): 1170–5. PMID 19033254.
- Nozu K, Iijima K, Nozu Y, et al. (2009). "A deep intronic mutation in the SLC12A3 gene leads to Gitelman syndrome". Pediatr. Res. 66 (5): 590–3. PMID 19668106.
- Ng DP, Nurbaya S, Choo S, et al. (2008). "Genetic variation at the SLC12A3 locus is unlikely to explain risk for advanced diabetic nephropathy in Caucasians with type 2 diabetes". Nephrol. Dial. Transplant. 23 (7): 2260–4. PMID 18263927.
- Aoi N, Nakayama T, Sato N, et al. (2008). "Case-control study of the role of the Gitelman's syndrome gene in essential hypertension". Endocr. J. 55 (2): 305–10. PMID 18362449.
- Qin L, Shao L, Ren H, et al. (2009). "Identification of five novel variants in the thiazide-sensitive NaCl co-transporter gene in Chinese patients with Gitelman syndrome". Nephrology (Carlton). 14 (1): 52–8. S2CID 38008467.
- Ridker PM, Paré G, Parker AN, et al. (2009). "Polymorphism in the CETP gene region, HDL cholesterol, and risk of future myocardial infarction: Genomewide analysis among 18 245 initially healthy women from the Women's Genome Health Study". Circ Cardiovasc Genet. 2 (1): 26–33. PMID 20031564.
- Richardson C, Rafiqi FH, Karlsson HK, et al. (2008). "Activation of the thiazide-sensitive Na+-Cl− cotransporter by the WNK-regulated kinases SPAK and OSR1". J. Cell Sci. 121 (Pt 5): 675–84. S2CID 33009059.
- Wang XF, Lin RY, Wang SZ, et al. (2008). "Association study of variants in two ion-channel genes (TSC and CLCNKB) and hypertension in two ethnic groups in Northwest China". Clin. Chim. Acta. 388 (1–2): 95–8. PMID 17997379.
- Miao Z, Gao Y, Bindels RJ, et al. (2009). "Coexistence of normotensive primary aldosteronism in two patients with Gitelman's syndrome and novel thiazide-sensitive Na–Cl cotransporter mutations". Eur. J. Endocrinol. 161 (2): 275–83. PMID 19451210.
- Zhan YY, Jiang X, Lin G, et al. (2007). "[Association of thiazide-sensitive Na+-Cl* cotransporter gene polymorphisms with the risk of essential hypertension]". Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 24 (6): 703–5. PMID 18067089.
External links
- Sodium+Chloride+Symporters at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Sodium+Chloride+Symporter+Inhibitors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)