Alternative titles; symbols
HGNC Approved Gene Symbol: MMP1
Cytogenetic location: 11q22.2 Genomic coordinates (GRCh38): 11:102,789,919-102,798,160 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q22.2 | {Epidermolysis bullosa dystrophica, autosomal recessive, modifier of} | 226600 | Autosomal recessive | 3 |
| COPD, rate of decline of lung function in | 606963 | 3 |
Matrix metalloproteinases are zinc-dependent proteases that degrade extracellular matrix proteins. MMP1 is also known as collagenase (EC 3.4.23.7) (Nagase et al., 1992).
Brinckerhoff et al. (1987) identified a cDNA clone of human collagenase. The clone identified a single collagenase gene of about 17 kb from blots of human genomic DNA. Restriction enzyme analysis and DNA sequence data indicated that the cDNA clone was full length and that it was identical to that described for human skin fibroblast collagenase. Collagenase is the only enzyme able to initiate breakdown of the interstitial collagens, types I, II, and III. The fact that the collagens are the most abundant proteins in the body means that collagenase plays a key role in the remodeling that occurs constantly in both normal and diseased conditions. The identity of human skin and synovial cell collagenase and the ubiquity of this enzyme and of its substrates, collagens I, II, and III, imply that the common mechanism controlling collagenolysis throughout the body may be operative in both normal and disease states.
Gerhard et al. (1987) confirmed the assignment of the collagenase gene to chromosome 11 by the use of a DNA probe for Southern analysis of somatic cell hybrids. Analysis of cell lines with rearrangements involving chromosome 11 indicated that the gene is in the region 11q11-q23. Church et al. (1983) had used somatic cell hybrids between mouse cells and human normal skin and corneal fibroblasts and recessive dystrophic epidermolysis bullosa (RDEB; 226600) skin fibroblasts to assign the human structural gene for collagenase to chromosome 11. Production of collagenase was measured by a specific radioimmunoassay. It appeared that both the normal and the RDEB collagenase gene mapped to chromosome 11. This was earlier taken to indicate that the abnormal collagenase produced by RDEB cells represented a mutation of the structural gene. Later work indicated that both the autosomal dominant (131750) and autosomal recessive forms of dystrophic epidermolysis bullosa are due to mutations in the type VII collagen gene (COL7A1; 120120). The excessive formation of collagenase must represent a secondary phenomenon, not the primary defect. It should be noted that fibroblasts from patients with the Werner syndrome (277700) also express high constitutive levels of collagenase in vitro (Bauer et al., 1986).
Pendas et al. (1996) isolated a 1.5-Mb YAC clone mapping to 11q22. Detailed analysis of this nonchimeric YAC clone ordered 7 MMP genes as follows: cen--MMP8 (120355)--MMP10 (185260)--MMP1--MMP3 (185250)--MMP12 (601046)--MMP7 (178990)--MMP13 (600108)--tel.
Maymon et al. (2000) measured levels of MMP1 in amniotic fluid from 353 women, including those with intact membranes, in term or preterm labor or not in labor, and those with term and premature rupture of the membranes (610504), with or without microbial invasion of the amniotic cavity. MMP1 was detectable in 81.3% (287 of 353) amniotic fluid samples, and the concentration increased with increasing gestational age. Analysis of the matrix metalloproteinase profile of amniotic fluid in term and preterm rupture of membranes showed that patterns were similar for every enzyme except MMP1 and MMP8 (120355), suggesting different molecular pathophysiologic mechanisms for extracellular matrix degradation of rupture of membranes in term and preterm gestations. Maymon et al. (2000) concluded that MMP1 is implicated in the mechanisms of membrane rupture.
Lahmann et al. (2001) found significantly more MMP1 mRNA in the buttock skin of smokers than nonsmokers and suggested that smoking-induced MMP1 might be important in the skin-aging effects of tobacco smoking.
Saffarian et al. (2004) showed that activated collagenase (MMP1) moves processively on the collagen fibril. The mechanism of movement is a biased diffusion with the bias component dependent on the proteolysis of its substrate, not ATP hydrolysis. Inactivation of the enzyme by a single amino acid residue substitution in the active center eliminated the bias without noticeable effect on rate of diffusion. Monte Carlo simulations using a model similar to a 'burnt bridge' Brownian ratchet accurately described the experimental result and previous observations on kinetics of collagen digestion. Saffarian et al. (2004) concluded that the biologic implications of MMP1 acting as a molecular ratchet tethered to the cell surface suggested novel mechanisms for its role in tissue remodeling and cell-matrix interaction.
Boire et al. (2005) found that expression of PAR1 (F2R; 187930) was both required and sufficient to promote growth and invasion of breast carcinoma cells in a xenograft mouse model. MMP1 acted as a protease agonist of PAR1, cleaving the receptor at the proper site to generate PAR1-dependent Ca(2+) signals and migration. MMP1 activity was derived from fibroblasts and was absent from the breast cancer cells. These results demonstrated that MMP1 in the stromal-tumor microenvironment can alter the behavior of cancer cells through PAR1 to promote cell migration and invasion.
By in vivo selection, transcriptomic analysis, functional verification, and clinical validation, Minn et al. (2005) identified a set of genes that marks and mediates breast cancer metastasis to the lungs. Some of these genes serve dual functions, providing growth advantages both in the primary tumor and in the lung microenvironment. Others contribute to aggressive growth selectivity in the lung. Among the lung metastasis signature genes identified, several, including MMP1 (p less than 0.000001), were functionally validated. Two that were not functionally validated but that achieved the highest statistical significance (p less than 0.000001) were FSCN1 (602689) and angiopoietin-like 4 (ANGPTL4; 605910). Those subjects expressing the lung metastasis signature had a significantly poorer lung metastasis-free survival, but not bone metastasis-free survival, compared to subjects without the signature.
Metastasis entails numerous biologic functions that collectively enable cancerous cells from a primary site to disseminate and overtake distant organs. Using genetic and pharmacologic approaches, Gupta et al. (2007) showed that the epidermal growth factor receptor ligand epiregulin (602061), the cyclooxygenase COX2 (600262), and the matrix metalloproteinases MMP1 and MMP2 (120360), when expressed in human breast cancer cells, collectively facilitate the assembly of new tumor blood vessels, the release of tumor cells into the circulation, and the breaching of lung capillaries by circulating tumor cells to seed pulmonary metastasis. Gupta et al. (2007) concluded that their findings revealed how aggressive primary tumorigenic functions can be mechanistically coupled to greater lung metastatic potential, and how such biologic activities can be therapeutically targeted with specific drug combinations.
Associations Pending Confirmation
Joos et al. (2002) found an association between a 1-bp insertion polymorphism in the MMP1 gene (G-1607GG; 120353.0001) and the rate of decline of lung function in chronic obstructive pulmonary disease (COPD; 606963).
Fujimoto et al. (2002) analyzed the G-1607GG promoter polymorphism in the MMP1 gene in 75 African American infants who were born after preterm premature rupture of the membranes (PPROM; 610504) and 235 controls, and found a significant association between fetal carriage of a 2G allele and PPROM (OR = 2.29; p = 0.028).
In studies in amnion fibroblasts, Wang et al. (2008) found that inhibition of DNA methylation resulted in significantly increased MMP1 gene transcription and an associated significant increase in MMP1 production. These effects were correlated with reduced DNA methylation at a specific site, -1538C, in the MMP1 promoter, and DNA methylation at that site was reduced in a larger percentage of fetal membranes that ruptured prematurely. The authors identified another SNP, 3447T-C (numbering based on AF007878.1; rs2075847), and observed that the minor C allele was always methylated in vivo and that methylation resulted in increased affinity for a nuclear protein in amnion fibroblasts. Plasmid transfection studies and chromatin immunoprecipitation assays demonstrated reduced promoter activity of the minor C allele. In a case-control study involving 284 African American neonates from pregnancies complicated by PPROM and 361 African American neonates from normal term pregnancies, Wang et al. (2008) found the minor C allele to be protective against PPROM (OR = 0.7451; p = 0.0326), consistent with its reduced promoter function. Neonates homozygous for the major T allele had 3.51-higher risk for PPROM compared to CC homozygotes (p = 0.007). Wang et al. (2008) concluded that, in addition to genetic variation, DNA methylation plays a role in controlling MMP1 expression and risk of PPROM.
Titeux et al. (2008) demonstrated that the G-1607GG polymorphism in MMP1 results in transcriptional upregulation. They found a significant association between this SNP and disease severity among patients with autosomal recessive dystrophic epidermolysis bullosa (RDEB; 226600).
This variant, formerly titled PULMONARY DISEASE, CHRONIC OBSTRUCTIVE, RATE OF DECLINE OF LUNG FUNCTION, with INCLUDED titles of Preterm Premature Rupture of the Membranes and Epidermolysis Bullosa Dystrophica, Autosomal Recessive, Modifier of, was reclassified as a polymorphism because the variant was present in 15,712 of 31,306 alleles and in homozygous state in 3,992 homozygotes in the gnomAD database (Hamosh, 2022).
Melanoma
Rutter et al. (1998) identified a SNP (rs1799750) in the promoter region of the MMP1 gene (position -1607) where an additional guanine nucleotide creates a binding site for members of the Ets family of transcription factors. The 2G SNP displayed significantly higher transcription in normal fibroblasts and in melanoma cells compared to the 1G SNP. The occurrence of 2G homozygotes was 30% in 100 CEPH controls; in tumor cell lines it was 62.5%. Rutter et al. (1998) suggested that increased MMP1 expression contributes to stromal degradation involved in tumor invasion.
Chronic Obstructive Pulmonary Disease, Rate of Decline of Lung Function in
Joos et al. (2002) investigated the role of MMP polymorphisms (including G-1607GG in MMP1 and N357S in MMP12) in the development of chronic obstructive pulmonary disease (see 606963). The authors determined the prevalence of these polymorphisms in 590 continuing smokers chosen from the National Heart, Lung, and Blood Institute Lung Health Study for having the fastest (284 individuals) and slowest (306 individuals) 5-year rate of decline of lung function. Of 5 polymorphisms among 3 MMP loci, only G-1607GG was associated with a rate of decline in lung function. This allele was associated with a fast rate of decline (p = 0.02). However, haplotypes consisting of alleles from the G-1607GG and N357S polymorphisms were associated with rate of decline of lung function (p = 0.0007). Joos et al. (2002) concluded that polymorphisms in the MMP1 and MMP12 genes, but not MMP9, are either causative factors in smoking-related lung injury or are in linkage disequilibrium with causative polymorphisms.
Preterm Premature Rupture of the Membranes
Fujimoto et al. (2002) studied the G-1607GG promoter polymorphism in amnion-derived cells and found that the 2G promoter had more than 2-fold greater activity than the 1G allele. Induction of MMP1 mRNA by phorbol 12-myristate 13-acetate (PMA) was significantly greater in cells with a 1G/2G or 2G/2G genotype compared to cells homozygous for the 1G allele. Analysis in 75 African American infants who were born after preterm premature rupture of the membranes (PPROM; 610504) and 235 controls demonstrated a significant association between fetal carriage of a 2G allele and PPROM (OR = 2.29; p = 0.028). The authors concluded that the 2G allele has stronger promoter activity in amnion cells, that it confers increased responsiveness of amnion cells to stimuli that induce MMP1, and that this polymorphism contributes to the risk of PPROM.
Epidermolysis Bullosa Dystrophica, Modifier of
Titeux et al. (2008) demonstrated that the G-1607GG polymorphism in MMP1 results in transcriptional upregulation. The authors found a significant association between this SNP and disease severity among patients with autosomal recessive dystrophic epidermolysis bullosa (RDEB; 226600). In 3 affected sibs and a follow-up cohort of 31 unrelated French patients, the functional SNP resulting in increased collagenase activity was associated with a more severe phenotype (p = 6.27 x 10(-5)). Titeux et al. (2008) concluded that increased MMP1 leads to increased collagen degradation and worsening disease severity, suggesting that MMP1 is a modifier gene in RDEB.
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