Carbonic anhydrase 12

CA12
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1JCZ, 1JD0, 4HT2, 4KP5, 4KP8, 4Q0L, 4QJ0, 4QJO, 4QJW, 4WW8
Identifiers
Aliases	CA12, CAXII, HsT18816, CA-XII, T18816, carbonic anhydrase 12
External IDs	OMIM: 603263 MGI: 1923709 HomoloGene: 20327 GeneCards: CA12
Gene location (Human) Chr. Chromosome 15 (human)[1] Band 15q22.2 Start 63,321,378 bp[1] End 63,381,846 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9|9 C Start 66,620,968 bp[2] End 66,674,127 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in renal medulla kidney tubule vulva glomerulus nipple metanephric glomerulus rectum human penis kidney skin of abdomen Top expressed in retinal pigment epithelium stria vascularis lip parotid gland kidney submandibular gland lacrimal gland esophagus conjunctival fornix utricle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function carbonate dehydratase activity zinc ion binding lyase activity metal ion binding carbonic anhydrase Cellular component integral component of membrane plasma membrane membrane Biological process bicarbonate transport chloride ion homeostasis Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 9: 66.62 – 66.67 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/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

• Sahin U, Türeci O, Schmitt H, Cochlovius B, Johannes T, Schmits R, Stenner F, Luo G, Schobert I, Pfreundschuh M (1996). "Human neoplasms elicit multiple specific immune responses in the autologous host". Proc. Natl. Acad. Sci. U.S.A. 92 (25): 11810–11813. Bibcode:1995PNAS...9211810S. doi:10.1073/pnas.92.25.11810. PMC 40492. PMID 8524854.
• Ivanov SV, Kuzmin I, Wei MH, Pack S, Geil L, Johnson BE, Stanbridge EJ, Lerman MI (1998). "Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel-Lindau transgenes". Proc. Natl. Acad. Sci. U.S.A. 95 (21): 12596–12601. Bibcode:1998PNAS...9512596I. doi:10.1073/pnas.95.21.12596. PMC 22876. PMID 9770531.
• 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. PMID 10512682.
• 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. PMID 10611263.
• Kivelä A, Parkkila S, Saarnio J, Karttunen TJ, Kivelä J, Parkkila AK, Waheed A, Sly WS, Grubb JH, Shah G, Türeci O, Rajaniemi H (2000). "Expression of a novel transmembrane carbonic anhydrase isozyme XII in normal human gut and colorectal tumors". Am. J. Pathol. 156 (2): 577–84. doi:10.1016/S0002-9440(10)64762-1. PMC 1850052. PMID 10666387.
• 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. PMID 11083462. S2CID 22170460.
• 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. PMID 11101628.
• Wykoff CC, Beasley N, Watson PH, Campo L, Chia SK, English R, Pastorek J, Sly WS, Ratcliffe P, Harris AL (2001). "Expression of the hypoxia-inducible and tumor-associated carbonic anhydrases in ductal carcinoma in situ of the breast". Am. J. Pathol. 158 (3): 1011–9. doi:10.1016/S0002-9440(10)64048-5. PMC 1850356. PMID 11238049.
• 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. PMID 11420383.
• Whittington DA, Waheed A, Ulmasov B, Shah GN, Grubb JH, Sly WS, Christianson DW (2001). "Crystal structure of the dimeric extracellular domain of human carbonic anhydrase XII, a bitopic membrane protein overexpressed in certain cancer tumor cells". Proc. Natl. Acad. Sci. U.S.A. 98 (17): 9545–9550. Bibcode:2001PNAS...98.9545W. doi:10.1073/pnas.161301298. PMC 55489. PMID 11493685.
• 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. PMID 11680594. S2CID 40928937.
• Liao SY, Ivanov S, Ivanova A, Ghosh S, Cote MA, Keefe K, Coca-Prados M, Stanbridge EJ, Lerman MI (2003). "Expression of cell surface transmembrane carbonic anhydrase genes CA9 and CA12 in the human eye: overexpression of CA12 (CAXII) in glaucoma". J. Med. Genet. 40 (4): 257–261. doi:10.1136/jmg.40.4.257. PMC 1735430. PMID 12676895.
• 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. doi:10.3748/wjg.v9.i7.1398. PMC 4615471. PMID 12854129.
• 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. PMID 12923247.
• 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. PMID 14578124.
• 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. doi:10.3748/wjg.v11.i17.2616. PMC 4305753. PMID 15849821.