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.[2]
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 [3][4][5][6][7][8]
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.[10]
However, CAXII mutant enzymes show reduced activity. These observations made it very hard to explain the mechanism for the autosomal recessive disorder of hyponatremia, causing salt wasting in sweat due to mutant CAXII.[3][4]
In a separate study, researchers observed that mutant enzyme activity is completely reduced at physiological concentrations of sodium chloride.[10] Thus, loss of the function of CAXII in sweat glands and lungs is the molecular basis for cystic fibrosis patients with normal CFTR levels.[10]
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.[12] CAXII specific inhibition provides a tool to interfere with cell proliferation, resulting in cell apoptosis in T-cell lymphomas.[13]
Analytical, Diagnostic, and Therapeutic Context of CAXII
Serum CAXII levels should be applicable as a sero-diagnostic marker for lung cancer.[14]
↑ 4.04.1Muhammad, 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. PMID21184099.
↑ 5.05.1Hong, 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. PMID26486891.
↑ 6.06.1Lee, 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: 1923–1933. doi:10.1093/hmg/ddw065. PMID26911677.
↑ 7.07.1Purkerson, 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. PMID17164835.
↑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. PMID11083462.
↑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. PMID12711377.
Fujikawa-Adachi K, Nishimori I, Taguchi T, Onishi S (1999). "Human carbonic anhydrase XIV (CA14): cDNA cloning, mRNA expression, and mapping to chromosome 1". Genomics. 61 (1): 74–81. doi:10.1006/geno.1999.5938. PMID10512682.
Karhumaa P, Parkkila S, Türeci O, Waheed A, Grubb JH, Shah G, Parkkila A, Kaunisto K, Tapanainen J, Sly WS, Rajaniemi H (2000). "Identification of carbonic anhydrase XII as the membrane isozyme expressed in the normal human endometrial epithelium". Mol. Hum. Reprod. 6 (1): 68–74. doi:10.1093/molehr/6.1.68. PMID10611263.
Kivelä AJ, Parkkila S, Saarnio J, Karttunen TJ, Kivelä J, Parkkila AK, Pastoreková S, Pastorek J, Waheed A, Sly WS, Rajaniemi H (2001). "Expression of transmembrane carbonic anhydrase isoenzymes IX and XII in normal human pancreas and pancreatic tumours". Histochem. Cell Biol. 114 (3): 197–204. doi:10.1007/s004180000181. PMID11083462.
Parkkila S, Parkkila AK, Saarnio J, Kivelä J, Karttunen TJ, Kaunisto K, Waheed A, Sly WS, Türeci O, Virtanen I, Rajaniemi H (2001). "Expression of the membrane-associated carbonic anhydrase isozyme XII in the human kidney and renal tumors". J. Histochem. Cytochem. 48 (12): 1601–8. doi:10.1177/002215540004801203. PMID11101628.
Karhumaa P, Kaunisto K, Parkkila S, Waheed A, Pastoreková S, Pastorek J, Sly WS, Rajaniemi H (2001). "Expression of the transmembrane carbonic anhydrases, CA IX and CA XII, in the human male excurrent ducts". Mol. Hum. Reprod. 7 (7): 611–616. doi:10.1093/molehr/7.7.611. PMID11420383.
Kivela AJ, Saarnio J, Karttunen TJ, Kivelä J, Parkkila AK, Pastorekova S, Pastorek J, Waheed A, Sly WS, Parkkila TS, Rajaniemi H (2001). "Differential expression of cytoplasmic carbonic anhydrases, CA I and II, and membrane-associated isozymes, CA IX and XII, in normal mucosa of large intestine and in colorectal tumors". Dig. Dis. Sci. 46 (10): 2179–2186. doi:10.1023/A:1011910931210. PMID11680594.
Leppilampi M, Saarnio J, Karttunen TJ, Kivelä J, Pastoreková S, Pastorek J, Waheed A, Sly WS, Parkkila S (2003). "Carbonic anhydrase isozymes IX and XII in gastric tumors". World J. Gastroenterol. 9 (7): 1398–403. PMID12854129.
Kyllönen MS, Parkkila S, Rajaniemi H, Waheed A, Grubb JH, Shah GN, Sly WS, Kaunisto K (2003). "Localization of carbonic anhydrase XII to the basolateral membrane of H+-secreting cells of mouse and rat kidney". J. Histochem. Cytochem. 51 (9): 1217–24. doi:10.1177/002215540305100912. PMID12923247.
Tarun AS, Bryant B, Zhai W, Solomon C, Shusterman D (2004). "Gene expression for carbonic anhydrase isoenzymes in human nasal mucosa". Chem. Senses. 28 (7): 621–629. doi:10.1093/chemse/bjg054. PMID14578124.
Kivela AJ, Parkkila S, Saarnio J, Karttunen TJ, Kivela J, Parkkila AK, Bartosova M, Mucha V, Novak M, Waheed A, Sly WS, Rajaniemi H, Pastorekova S, Pastorek J (2005). "Expression of von Hippel-Lindau tumor suppressor and tumor-associated carbonic anhydrases IX and XII in normal and neoplastic colorectal mucosa". World J. Gastroenterol. 11 (17): 2616–25. PMID15849821.
