Disease relevance of CMA1

• OBJECTIVE: It has been suspected that the mast cell chymase gene (CMA1) is important for the generation of angiotensin II and therefore might be associated with the pathogenesis of hypertension [1].
• METHODS: We sequenced the CMA1 locus in 24 unrelated healthy individuals with serum IgE levels <50% percentile and 24 individuals with atopic eczema and serum IgE levels >90% percentile [2].
• A significant association was found between CMA1 genotypes and total IgE levels in subjects with self-reported eczema that remained significant after correction for multiple testing (median total serum IgE GG 297 kU/L, GA 144 kU/L, AA 48.4 kU/L, Pc=0.0032) [3].
• Chymase Gene (CMA1) Polymorphisms in Dutch and Japanese Sarcoidosis Patients [4].
• However, the association between CMA1 -526 C/T and iVC in the Dutch patients suggests that chymase may modify the functional outcome of pulmonary sarcoidosis [4].

High impact information on CMA1

• TMA20 has significant sequence homology with the oncogene MCT-1 [5].
• In this study, we determined the regulatory elements contained within the CYM promoter by using a luciferase reporter gene [6].
• MCT-1 is an oncogene that was initially identified in a human T cell lymphoma and has been shown to induce cell proliferation as well as activate survival-related pathways [7].
• In the stomach, MCT1 was present on the basolateral surfaces of epithelial cells; in contrast, MCT2 was expressed on parietal cells of the oxyntic gland [8].
• Like MCT1, MCT2 transported pyruvate and lactate [8].

Chemical compound and disease context of CMA1

• The H+-Linked Monocarboxylate Transporter (MCT1/SLC16A1): A Potential Therapeutic Target for High-Risk Neuroblastoma [9].
• Neuroblastomas produce high amounts of lactic acid and upregulate the H(+)-linked monocarboxylate transporter isoform 1 (MCT1/SLC16A1) [9].

Biological context of CMA1

• Heterozygous disruption of CMA1 does not affect blood pressure [1].
• METHODS: We sequenced the promoter region, exons, and exon-intron junctions of CMA1 and found 13 single-nucleotide polymorphisms, two of which were loss-of-function mutations [1].
• The human mast cell chymase gene (CMA1): mapping to the cathepsin G/granzyme gene cluster and lineage-restricted expression [10].
• Associations analyses between the promoter polymorphism rs1800875 in the mast cell chymase gene (CMA1) and atopy-related phenotypes have yielded inconsistent results [2].
• Seven CMA1 single nucleotide polymorphisms (SNPs) were evaluated for evidence of associations with atopic phenotypes within a large population of German adults (n = 1875) [2].

Anatomical context of CMA1

• Cellular invasion assays correlate with gene expression and zymography experiments identifying both Ox and MCT-1 as able to inhibit invasion of metastatic cancer cell lines through matrigel at nanomolar concentrations, with MCT-1 more effective than Ox in 2 of the 3 cancer cell lines assessed [11].
• At this stage, less than 10% of vessels in the ventricular layer expressed MCT1, whereas all blood vessels walls showed this immunoreactivity at the 26th gestational week [12].
• We investigated the immunocytochemical expression of two monocarboxylate transporters, MCT1 and MCT2, in the human visual cortex between 13 and 26 post-ovulatory weeks [12].
• Our findings suggest that monocarboxylate trafficking between vessels (MCT1), astrocytes (MCT2) and some postmitotic neurons (MCT1) could develop gradually toward 20 gestational weeks (g.w.). These data suggest that lactate or other monocarboxylates could represent a significant energy source for the human visual cortex at this early stage [12].
• MCT1 was present in erythrocytes and on the basolateral surfaces of intestinal epithelial cells [8].

Associations of CMA1 with chemical compounds

• Immunofluorescence microscopy shows that MCT1 expression is restricted to the intercalated disk region, yet the rate of lactate transport in this region is slower than in the center of the cell, where there is no MCT1 [13].
• MCT1, but not MCT2, was sensitive to organomercurial thiol reagents such as p-chloromercuribenzoic acid [8].
• The mucosal MCT1 was localized in the basolateral membrane of enterocytes, while slc5a8 was restricted to the apical cell membrane, suggesting the involvement of slc5a8 in the uptake of luminal SCFA, and of MCT1 in the efflux of SCFA and monocarboxylate metabolites towards blood circulation [14].
• We analyzed DNA duplexes modified at central guanine residues by monofunctional Ru(II) arene complexes [(eta(6)-arene)Ru(II)(en)(Cl)](+) (arene = tetrahydroanthracene or p-cymene, Ru-THA or Ru-CYM, respectively) [15].
• We have previously described a novel series of potent blockers of the monocarboxylate transporter, MCT1, which show potent immunomodulatory activity in an assay measuring inhibition of PMA/ionomycin-induced human PBMC proliferation [16].
• Exogenous peroxynitrite but not hydrogen peroxide also resulted in chymase activation in unwounded monolayers [17].

Other interactions of CMA1

• 2. The current work identifies the human mast cell chymase gene (CMA1) as the fourth protease in this cluster and maps the gene to within 150 kb of the cathepsin G gene [10].
• Starting at the 19th week of gestation, sparse MCT1 positive cell bodies were detected, some of them co-localized with MAP2 immunoreactivity [12].
• The results of these experiments suggest the presence of 2 different transporter isoforms in heart cells, at least one of which is different from the cloned MCT1 and MCT2 [13].
• For the CMA1, AGT and AT2R1 genes we have not found significant differences in allele/genotype distribution [18].

Analytical, diagnostic and therapeutic context of CMA1

• New cDNA sequences with strong homology to MCT1 have been found in human cDNA libraries and Northern blots show that the corresponding mRNA is expressed in rat heart [13].
• RT-PCR revealed the presence of transcripts for the MCT subtypes MCT1 and MCT2 [19].
• RT-PCR performed with primers for the MCT1 and MCT2 subtypes on total RNA from stria vascularis revealed PCR products of the predicted sizes [20].

References