Carbonic anhydrase 12

Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in various 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 highly expressed in normal tissues, such as kidney, colon and pancreas, and has been overexpressed in 10% of clear cell renal carcinomas. Two transcript variants encoding different isoforms have been identified for this gene.

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 {{cite journal|last1=Feldshtein|first1=M|last2=Elkrinawi|first2=S|last3=Yerushalmi|first3=B|last4=Marcus|first4=B|last5=Vullo|first5=D|last6=Romi|first6=H|last7=Ofir|first7=R|last8=Landau|first8=D|last9=Sivan|first9=S|last10=Supuran|first10=CT|last11=Birk|first11=OS|title=Hyperchlorhidrosis caused by homozygous mutation in CA12, encoding carbonic anhydrase XII.|journal=American Journal of Human Genetics|date=12 November 2010|volume=87|issue=5|pages=713–20|pmid=21035102|doi=10.1016/j.ajhg.2010.10.008|pmc=2978943}}{{cite journal|last1=Muhammad|first1=E|last2=Leventhal|first2=N|last3=Parvari|first3=G|last4=Hanukoglu|first4=A|last5=Hanukoglu|first5=I|last6=Chalifa-Caspi|first6=V|last7=Feinstein|first7=Y|last8=Weinbrand|first8=J|last9=Jacoby|first9=H|last10=Manor|first10=E|last11=Nagar|first11=T|last12=Beck|first12=JC|last13=Sheffield|first13=VC|last14=Hershkovitz|first14=E|last15=Parvari|first15=R|title=Autosomal recessive hyponatremia due to isolated salt wasting in sweat associated with a mutation in the active site of Carbonic Anhydrase 12.|journal=Human Genetics|date=April 2011|volume=129|issue=4|pages=397–405|pmid=21184099|doi=10.1007/s00439-010-0930-4|s2cid=11034371}}{{cite journal|last1=Hong|first1=JH|last2=Muhammad|first2=E|last3=Zheng|first3=C|last4=Hershkovitz|first4=E|last5=Alkrinawi|first5=S|last6=Loewenthal|first6=N|last7=Parvari|first7=R|last8=Muallem|first8=S|title=Essential role of carbonic anhydrase XII in secretory gland fluid and HCO3 (-) secretion revealed by disease causing human mutation.|journal=The Journal of Physiology|date=15 December 2015|volume=593|issue=24|pages=5299–312|pmid=26486891|doi=10.1113/jp271378|pmc=4704518}}{{cite journal|last1=Lee|first1=M|last2=Vecchio-Pagán|first2=B|last3=Sharma|first3=N|last4=Waheed|first4=A|last5=Li|first5=X|last6=Raraigh|first6=KS|last7=Robbins|first7=S|last8=Han|first8=ST|last9=Franca|first9=AL|last10=Pellicore|first10=MJ|last11=Evans|first11=TA|last12=Arcara|first12=KM|last13=Nguyen|first13=H|last14=Luan|first14=S|last15=Belchis|first15=D|last16=Hertecant|first16=J|last17=Zabner|first17=J|last18=Sly|first18=WS|last19=Cutting|first19=GR|title=Loss of carbonic anhydrase XII function in individuals with elevated sweat chloride concentration and pulmonary airway disease.|journal=Human Molecular Genetics|date=23 February 2016|pmid=26911677|pmc=5062583|doi=10.1093/hmg/ddw065|volume=25|issue=10|pages=1923–1933}}{{cite journal|last1=Purkerson|first1=JM|last2=Schwartz|first2=GJ|title=The role of carbonic anhydrases in renal physiology.|journal=Kidney International|date=January 2007|volume=71|issue=2|pages=103–15|pmid=17164835|doi=10.1038/sj.ki.5002020|doi-access=free}}{{cite journal|last1=Quinton|first1=PM|title=Role of epithelial HCO3⁻ transport in mucin secretion: lessons from cystic fibrosis.|journal=American Journal of Physiology. Cell Physiology|date=December 2010|volume=299|issue=6|pages=C1222–33|pmid=20926781|doi=10.1152/ajpcell.00362.2010|pmc=3006319}}

2) Pancreatitis{{cite journal|last1=Kivelä|first1=AJ|last2=Parkkila|first2=S|last3=Saarnio|first3=J|last4=Karttunen|first4=TJ|last5=Kivelä|first5=J|last6=Parkkila|first6=AK|last7=Pastoreková|first7=S|last8=Pastorek|first8=J|last9=Waheed|first9=A|last10=Sly|first10=WS|last11=Rajaniemi|first11=H|title=Expression of transmembrane carbonic anhydrase isoenzymes IX and XII in normal human pancreas and pancreatic tumours.|journal=Histochemistry and Cell Biology|date=September 2000|volume=114|issue=3|pages=197–204|pmid=11083462|doi=10.1007/s004180000181|s2cid=22170460}}{{cite journal|last1=Lee|first1=MG|last2=Ohana|first2=E|last3=Park|first3=HW|last4=Yang|first4=D|last5=Muallem|first5=S|title=Molecular mechanism of pancreatic and salivary gland fluid and HCO3 secretion.|journal=Physiological Reviews|date=January 2012|volume=92|issue=1|pages=39–74|pmid=22298651|doi=10.1152/physrev.00011.2011|pmc=3667394}}

3) Sjögren's syndrome{{cite journal|last1=Almståhl|first1=A|last2=Wikström|first2=M|title=Electrolytes in stimulated whole saliva in individuals with hyposalivation of different origins.|journal=Archives of Oral Biology|date=May 2003|volume=48|issue=5|pages=337–44|pmid=12711377|doi=10.1016/s0003-9969(02)00200-5}}

4) Xerostomia or dry mouth 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.

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.

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

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.{{cite journal|last1=Manokaran|first1=S|last2=Zhang|first2=X|last3=Chen|first3=W|last4=Srivastava|first4=DK|title=Differential modulation of the active site environment of human carbonic anhydrase XII by cationic quantum dots and polylysine.|journal=Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics|date=June 2010|volume=1804|issue=6|pages=1376–84|pmid=20215053|doi=10.1016/j.bbapap.2010.02.014|pmc=3181075}} CAXII specific inhibition provides a tool to interfere with cell proliferation, resulting in cell apoptosis in T-cell lymphomas.{{cite journal|last1=Lounnas|first1=N|last2=Rosilio|first2=C|last3=Nebout|first3=M|last4=Mary|first4=D|last5=Griessinger|first5=E|last6=Neffati|first6=Z|last7=Chiche|first7=J|last8=Spits|first8=H|last9=Hagenbeek|first9=TJ|last10=Asnafi|first10=V|last11=Poulsen|first11=SA|last12=Supuran|first12=CT|last13=Peyron|first13=JF|last14=Imbert|first14=V|title=Pharmacological inhibition of carbonic anhydrase XII interferes with cell proliferation and induces cell apoptosis in T-cell lymphomas.|journal=Cancer Letters|date=1 June 2013|volume=333|issue=1|pages=76–88|pmid=23348702|doi=10.1016/j.canlet.2013.01.020|url=https://zenodo.org/record/3415870}}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }}

Serum CAXII levels should be applicable as a sero-diagnostic marker for lung cancer.{{cite journal|last1=Kobayashi|first1=M|last2=Matsumoto|first2=T|last3=Ryuge|first3=S|last4=Yanagita|first4=K|last5=Nagashio|first5=R|last6=Kawakami|first6=Y|last7=Goshima|first7=N|last8=Jiang|first8=SX|last9=Saegusa|first9=M|last10=Iyoda|first10=A|last11=Satoh|first11=Y|last12=Masuda|first12=N|last13=Sato|first13=Y|title=CAXII Is a sero-diagnostic marker for lung cancer.|journal=PLOS ONE|date=2012|volume=7|issue=3|pages=e33952|pmid=22439015|doi=10.1371/journal.pone.0033952|pmc=3306309|bibcode=2012PLoSO...733952K|doi-access=free}}

{{Academic-written review|Q=Q39256524}}

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• {{UCSC gene info|CA12}}

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