CA12
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCA12, CAXII, HsT18816, CA-XII, T18816, carbonic anhydrase 12
External IDsOMIM: 603263 MGI: 1923709 HomoloGene: 20327 GeneCards: CA12
Orthologs
SpeciesHumanMouse
Entrez

771

76459

Ensembl

ENSG00000074410

ENSMUSG00000032373

UniProt

O43570

Q8CI85

RefSeq (mRNA)

NM_206925
NM_001218
NM_001293642

NM_178396
NM_001306148

RefSeq (protein)

NP_001209
NP_001280571
NP_996808

NP_001293077
NP_848483

Location (UCSC)Chr 15: 63.32 – 63.38 MbChr 9: 66.62 – 66.67 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Carbonic anhydrase 12 is an enzyme that in humans is encoded by the CA12 gene.[5][6]

Function

Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid. This gene product is a type I membrane protein that is highly expressed in normal tissues, such as kidney, colon and pancreas, and has been found to be overexpressed in 10% of clear cell renal carcinomas. Two transcript variants encoding different isoforms have been identified for this gene.[6]

Pathology

Loss of function mutations in the CAXII gene result in defects in fluids and carbonate secretions in the following diseases:

1) Cystic fibrosis-like syndrome with normal cystic fibrosis transmembrane conductance regulator (CFTR) protein levels [7][8][9][10][11][12]

2) Pancreatitis[13][14]

3) Sjögren's syndrome[14][15]

4) Xerostomia or dry mouth syndrome[9][10][11]

Molecular Basis of Cystic Fibrosis-like Syndrome

CAXII, with either the His121Gln or Glu143Lys mutation, localizes to basolateral membranes of polarized MDCK cells similar to the wild type enzyme, indicating no deleterious effect on subcellular location.[14]

The Glu143Lys (E143K) loss-of-function variant of the CAXII gene is associated with a rare autosomal recessive condition named isolated hyperchlorhidrosis (carbonic anhydrase XII deficiency). Typically, this variant results in excessive sodium chloride loss, usually through sweating, and presents pathologically as episodic hyponatremic dehydration with bouts of vomiting and/or diarrhoea.

Generally, CAXII mutant enzymes show reduced activity. These observations make it difficult to explain the mechanism for the autosomal recessive disorder of hyponatremia, causing salt wasting in sweat due to mutant CAXII.[7][8]

In a separate study, researchers observed that mutant enzyme activity is completely reduced at physiological concentrations of sodium chloride.[14] Thus, loss of the function of CAXII in sweat glands and lungs is the molecular basis for cystic fibrosis patients with normal CFTR levels.[14]

High Impact Information on CAXII

Differential modulation of the active site environment of CAXII by cationic quantum dots and polylysine helps design CAXII specific activators and inhibitors of the enzyme.[16] CAXII specific inhibition provides a tool to interfere with cell proliferation, resulting in cell apoptosis in T-cell lymphomas.[17]

Analytical, Diagnostic, and Therapeutic Context of CAXII

Serum CAXII levels should be applicable as a sero-diagnostic marker for lung cancer.[18]

Notes

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000074410 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000032373 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Türeci O, Sahin U, Vollmar E, Siemer S, Göttert E, Seitz G, Parkkila AK, Shah GN, Grubb JH, Pfreundschuh M, Sly WS (Aug 1998). "Human carbonic anhydrase XII: cDNA cloning, expression, and chromosomal localization of a carbonic anhydrase gene that is overexpressed in some renal cell cancers". Proc Natl Acad Sci U S A. 95 (13): 7608–7613. Bibcode:1998PNAS...95.7608T. doi:10.1073/pnas.95.13.7608. PMC 22698. PMID 9636197.
  6. 1 2 "Entrez Gene: CA12 carbonic anhydrase XII".
  7. 1 2 Feldshtein, M; Elkrinawi, S; Yerushalmi, B; Marcus, B; Vullo, D; Romi, H; Ofir, R; Landau, D; Sivan, S; Supuran, CT; Birk, OS (12 November 2010). "Hyperchlorhidrosis caused by homozygous mutation in CA12, encoding carbonic anhydrase XII". American Journal of Human Genetics. 87 (5): 713–20. doi:10.1016/j.ajhg.2010.10.008. PMC 2978943. PMID 21035102.
  8. 1 2 Muhammad, E; Leventhal, N; Parvari, G; Hanukoglu, A; Hanukoglu, I; Chalifa-Caspi, V; Feinstein, Y; Weinbrand, J; Jacoby, H; Manor, E; Nagar, T; Beck, JC; Sheffield, VC; Hershkovitz, E; Parvari, R (April 2011). "Autosomal recessive hyponatremia due to isolated salt wasting in sweat associated with a mutation in the active site of Carbonic Anhydrase 12". Human Genetics. 129 (4): 397–405. doi:10.1007/s00439-010-0930-4. PMID 21184099. S2CID 11034371.
  9. 1 2 Hong, JH; Muhammad, E; Zheng, C; Hershkovitz, E; Alkrinawi, S; Loewenthal, N; Parvari, R; Muallem, S (15 December 2015). "Essential role of carbonic anhydrase XII in secretory gland fluid and HCO3 (-) secretion revealed by disease causing human mutation". The Journal of Physiology. 593 (24): 5299–312. doi:10.1113/jp271378. PMC 4704518. PMID 26486891.
  10. 1 2 Lee, M; Vecchio-Pagán, B; Sharma, N; Waheed, A; Li, X; Raraigh, KS; Robbins, S; Han, ST; Franca, AL; Pellicore, MJ; Evans, TA; Arcara, KM; Nguyen, H; Luan, S; Belchis, D; Hertecant, J; Zabner, J; Sly, WS; Cutting, GR (23 February 2016). "Loss of carbonic anhydrase XII function in individuals with elevated sweat chloride concentration and pulmonary airway disease". Human Molecular Genetics. 25 (10): 1923–1933. doi:10.1093/hmg/ddw065. PMC 5062583. PMID 26911677.
  11. 1 2 Purkerson, JM; Schwartz, GJ (January 2007). "The role of carbonic anhydrases in renal physiology". Kidney International. 71 (2): 103–15. doi:10.1038/sj.ki.5002020. PMID 17164835.
  12. ↑ Quinton, PM (December 2010). "Role of epithelial HCO3− transport in mucin secretion: lessons from cystic fibrosis". American Journal of Physiology. Cell Physiology. 299 (6): C1222–33. doi:10.1152/ajpcell.00362.2010. PMC 3006319. PMID 20926781.
  13. ↑ Kivelä, AJ; Parkkila, S; Saarnio, J; Karttunen, TJ; Kivelä, J; Parkkila, AK; Pastoreková, S; Pastorek, J; Waheed, A; Sly, WS; Rajaniemi, H (September 2000). "Expression of transmembrane carbonic anhydrase isoenzymes IX and XII in normal human pancreas and pancreatic tumours". Histochemistry and Cell Biology. 114 (3): 197–204. doi:10.1007/s004180000181. PMID 11083462. S2CID 22170460.
  14. 1 2 3 4 5 Lee, MG; Ohana, E; Park, HW; Yang, D; Muallem, S (January 2012). "Molecular mechanism of pancreatic and salivary gland fluid and HCO3 secretion". Physiological Reviews. 92 (1): 39–74. doi:10.1152/physrev.00011.2011. PMC 3667394. PMID 22298651.
  15. ↑ Almståhl, A; Wikström, M (May 2003). "Electrolytes in stimulated whole saliva in individuals with hyposalivation of different origins". Archives of Oral Biology. 48 (5): 337–44. doi:10.1016/s0003-9969(02)00200-5. PMID 12711377.
  16. ↑ Manokaran, S; Zhang, X; Chen, W; Srivastava, DK (June 2010). "Differential modulation of the active site environment of human carbonic anhydrase XII by cationic quantum dots and polylysine". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1804 (6): 1376–84. doi:10.1016/j.bbapap.2010.02.014. PMC 3181075. PMID 20215053.
  17. ↑ Lounnas, N; Rosilio, C; Nebout, M; Mary, D; Griessinger, E; Neffati, Z; Chiche, J; Spits, H; Hagenbeek, TJ; Asnafi, V; Poulsen, SA; Supuran, CT; Peyron, JF; Imbert, V (1 June 2013). "Pharmacological inhibition of carbonic anhydrase XII interferes with cell proliferation and induces cell apoptosis in T-cell lymphomas". Cancer Letters. 333 (1): 76–88. doi:10.1016/j.canlet.2013.01.020. PMID 23348702.
  18. ↑ Kobayashi, M; Matsumoto, T; Ryuge, S; Yanagita, K; Nagashio, R; Kawakami, Y; Goshima, N; Jiang, SX; Saegusa, M; Iyoda, A; Satoh, Y; Masuda, N; Sato, Y (2012). "CAXII Is a sero-diagnostic marker for lung cancer". PLOS ONE. 7 (3): e33952. Bibcode:2012PLoSO...733952K. doi:10.1371/journal.pone.0033952. PMC 3306309. PMID 22439015.

Further reading

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