Alternative titles; symbols
HGNC Approved Gene Symbol: CMA1
Cytogenetic location: 14q12 Genomic coordinates (GRCh38) : 14:24,505,353-24,508,265 (from NCBI)
Chymase-1 (CMA1) is released from mast cells after their activation and is involved in physiologic processes associated with the development of an acute inflammatory reponse and the cross-talk between neutrophils and platelets in the hemostatic process (summary by Chmelar et al., 2011).
Chymase is a major secreted protease of mast cells with suspected roles in vasoactive peptide generation, extracellular matrix degradation, and regulation of gland secretion. Caughey et al. (1991) cloned and sequenced a human chymase gene encoding a preproenzyme with a 19-amino acid signal peptide, an acidic 2-amino acid propeptide, and a 226-amino acid catalytic domain. In the phase and placement of introns, the organization of the human chymase gene is similar to that of several other granule-associated leukocyte serine proteases including lymphocyte granzymes (see 600311), neutrophil cathepsin G (CTSG; 116830), and elastase (130130). However, its organization differs from that of mast cell tryptase.
The heart, a target organ for angiotensin II (see 106150), has a dual pathway for its formation in which the major angiotensin II-forming enzymes are angiotensin I-converting enzyme (106180) and chymase. Compared to other chymases, human heart chymase has an unusually high degree of specificity for the substrate angiotensin I. Urata et al. (1991) cloned the gene for human heart chymase, the most catalytically efficient enzyme that had been described for the cleavage of angiotensin I to yield angiotensin II and the dipeptide his-leu. The deduced amino acid sequence showed a high degree of homology to other members of the chymase subfamily. However, this gene lacked mast cell-specific sequences found in the 5-prime and 3-prime untranslated regions of the rat chymase II gene. In addition, human heart chymase contained clusters of unique amino acid sequences located at key positions probably involved in substrate binding. Urata et al. (1993) performed in situ hybridization studies suggesting that cardiac mast cells, mesenchymal interstitial cells, and endothelial cells are the cellular sites of synthesis of angiotensin II and storage of chymase.
Ju et al. (2001) cloned a rat vascular chymase (RVCH) from smooth muscle cells (SMCs) that converts angiotensin I to II and is upregulated in SMC from spontaneously hypertensive versus normotensive rats. To determine whether increased activity of RVCH is sufficient to cause hypertension, transgenic mice were generated with targeted conditional expression of RVCH to SMC. Ju et al. (2001) confirmed conditional expression of RVCH in the absence, but not in the presence, of dietary doxycycline. Systolic, diastolic, and mean pressures were elevated in the transgenic mice. Hypertension was completely reversed by doxycycline, suggesting a causal link with chymase expression. Medial thickening of mesenteric arteries in the transgenic mice was associated with increased SMC proliferation. These structural changes were also prevented by doxycycline. Increased vasoconstriction in response to phenylephrine and impaired metacholine-induced vasodilatation could be demonstrated when compared with littermate controls or with the doxycycline-treated group. These studies suggested that upregulation of this vascular chymase is sufficient to cause hypertensive arteriopathy, and that RVCH may be a candidate gene and a therapeutic target in patients with high blood pressure.
Using a mouse model of acute inflammation, Chmelar et al. (2011) found that a salivary protein, termed Irs2, from the tick Ixodes ricinus, the vector for Lyme disease in Europe, inhibited edema formation and neutrophil influx in inflamed tissue. Using a panel of human proteins, they found that Irs2 primarily inhibited CTSG and CMA1. Human platelet aggregation assays showed that Irs2 inhibited CTSG-induced and thrombin (F2; 176930)-induced platelet aggregation. Structural analysis revealed that Irs2 resembles mammalian serpins, including bovine antithrombin III (SERPINC1; 107300) and human alpha-1-antichymotrypsin (SERPINA3; 107280) and alpha-1-antitrypsin (SERPINA1; 107400).
Sharma et al. (2005) studied the association of a polymorphism in the CMA1 gene, -1903G-A, and a (TG)n(GA)n repeat polymorphism located 254 bp downstream of the gene with asthma and IgE levels in Indian asthmatic patients with a family history of asthma and atopy (see 147050). A significant association was observed between -1903G-A genotype and serum IgE levels (p = 0.003 and p = 0.0004 for a northern and western cohort, respectively). Sharma et al. (2005) suggested that the CMA1 gene contributes to asthma susceptibility and may be involved in regulating IgE levels in atopic asthma.
By a study of hamster-human hybrid DNAs, Caughey et al. (1991) assigned the CMA1 gene to human chromosome 14, which is the site of related genes. From studies of YACs and cosmid clones, Caughey et al. (1993) demonstrated that the mast cell chymase gene is located at 14q11.2 in the same cluster as the genes for 3 other proteases, T-cell receptor alpha/delta (TCRA; see 186880/TCRD; see 186810), neutrophil cathepsin G, and the lymphocyte cathepsin G-like proteins CGL1 (123910) and CGL2 (116831). They found that CMA1 maps to a site within 150 kb of the cathepsin G gene. The gene order is: cen--TCRA/TCRD--CGL1--CGL2--CTSG--CMA. In some cells, the chymase and cathepsin G genes were cotranscribed; in others, they appeared to be capable of independent regulation.
Caughey, G. H., Schaumberg, T. H., Zerweck, E. H., Butterfield, J. H., Hanson, R. D., Silverman, G. A., Ley, T. J. The human mast cell chymase gene (CMA1): mapping to the cathepsin G/granzyme gene cluster and lineage-restricted expression. Genomics 15: 614-620, 1993. [PubMed: 8468056] [Full Text: https://doi.org/10.1006/geno.1993.1115]
Caughey, G. H., Zerweck, E. H., Vanderslice, P. Structure, chromosomal assignment, and deduced amino acid sequence of a human gene for mast cell chymase. J. Biol. Chem. 266: 12956-12963, 1991. [PubMed: 2071582]
Chmelar, J., Oliveira, C. J., Rezacova, P., Francischetti, I. M. B., Kovarova, Z., Pejler, G., Kopacek, P., Ribeiro, J. M. C., Mares, M., Kopecky, J., Kotsyfakis, M. A tick salivary protein targets cathepsin G and chymase and inhibits host inflammation and platelet aggregation. Blood 117: 736-744, 2011. [PubMed: 20940421] [Full Text: https://doi.org/10.1182/blood-2010-06-293241]
Ju, H., Gros, R., You, X., Tsang, S., Husain, M., Rabinovitch, M. Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice. Proc. Nat. Acad. Sci. 98: 7469-7474, 2001. [PubMed: 11416217] [Full Text: https://doi.org/10.1073/pnas.131147598]
Sharma, S., Rajan, U. M., Kumar, A., Soni, A., Ghosh, B. A novel (TG)n(GA)m repeat polymorphism 254 bp downstream of the mast cell chymase (CMA1) gene is associated with atopic asthma and total serum IgE levels. J. Hum. Genet. 50: 276-282, 2005. [PubMed: 15924217] [Full Text: https://doi.org/10.1007/s10038-005-0252-x]
Urata, H., Boehm, K. D., Philip, A., Kinoshita, A., Gabrovsek, J., Bumpus, F. M., Husain, A. Cellular localization and regional distribution of an angiotensin II-forming chymase in the heart. J. Clin. Invest. 91: 1269-1281, 1993. [PubMed: 7682566] [Full Text: https://doi.org/10.1172/JCI116325]
Urata, H., Kinoshita, A., Perez, D. M., Misono, K. S., Bumpus, F. M., Graham, R. M., Husain, A. Cloning of the gene and cDNA for human heart chymase. J. Biol. Chem. 266: 17173-17179, 1991. [PubMed: 1894611]