Alternative titles; symbols
HGNC Approved Gene Symbol: MMP14
SNOMEDCT: 254151006;
Cytogenetic location: 14q11.2 Genomic coordinates (GRCh38): 14:22,836,585-22,847,758 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q11.2 | Winchester syndrome | 277950 | Autosomal recessive | 3 |
Matrix metalloproteinases (MMPs) are Zn(2+)-binding endopeptidases that degrade various components of the extracellular matrix (ECM). The MMPs are enzymes implicated in normal and pathologic tissue remodeling processes, wound healing, angiogenesis, and tumor invasion. MMPs have different substrate specificities and are encoded by different genes. Sato et al. (1994) cloned a cDNA for the human gene from a placenta cDNA library (they called the gene MMP-X1 and the gene product membrane-type metalloproteinase). The authors noted that the protein was expressed at the surface of invasive tumor cells. Using degenerate PCR, Takino et al. (1995) cloned the entire genomic sequence of this member of the MMP superfamily (see MMP1; 120353). The cDNA identified codes for a 582-amino acid protein which shared conserved sequence and a similar domain structure to other MMPs. They noted that the cDNA, termed MMP-X1 by them, had a unique transmembrane domain at the C terminus. Thus, they predicted that MMP-X1 was a membrane spanning protein rather than a secretory protein like the other MMPs. Northern blots showed that MMP-X1 expression was present at varying intensity in almost all tissues examined, but was highest in the placenta.
By isotopic in situ hybridization, Mignon et al. (1995) mapped the MMP14 gene to chromosome 14q11-q12.
Mignon et al. (1995) tabulated 11 members of the matrix metalloproteinase family and their chromosomal locations; with 1 exception, the genes encoding them had been mapped. Six of them, including 3 collagenases and 2 stromelysins, had been assigned to 11q.
Mignon et al. (1995) stated that membrane-type matrix metalloproteinase (MMP14) may be an activator of pro-gelatinase A (MMP2; 120360) and is expressed in fibroblast cells during both wound healing and human cancer progression.
Ueda et al. (2002) investigated survivin gene and protein expression in a tumor-like benign disease, endometriosis, and correlated them with apoptosis and invasive phenotype of endometriotic tissues. Gene expression levels of survivin (603352), MMP2, MMP9 (120361), and MMP14 in 63 pigmented or nonpigmented endometriotic tissues surgically obtained from 35 women with endometriosis were compared with those in normal eutopic endometrium obtained from 12 women without endometriosis. Survivin, MMP2, MMP9, and MMP14 mRNA expression levels in clinically aggressive pigmented lesions were significantly higher than those in normal eutopic endometrium, and survivin gene expression in pigmented lesions was also higher than that in nonpigmented lesions (P less than 0.05). There was a close correlation between survivin and MMP2, MMP9, and MMP14 gene expression levels in 63 endometriotic tissues examined (P less than 0.01). The authors concluded that upregulation of survivin and MMPs may cooperatively contribute to survival and invasion of endometriosis.
Noda et al. (2003) studied MMPs and their activation in association with the pathogenesis of proliferative diabetic retinopathy (PDR; 603933). They demonstrated that pro-MMP2 was efficiently activated in the fibrovascular tissues of PDR, probably through interaction with MT1-MMP and TIMP2 (188825). The results suggested that MMP2 and MT1-MMP may be involved in the formation of the fibrovascular tissues.
Hotary et al. (2003) found that MT1-MMP conferred human tumor cell lines with a 3-dimensional growth advantage in vitro and in vivo. The replicative advantage conferred by MT1-MMP required pericellular proteolysis of the extracellular matrix, as proliferation was suppressed by protease-resistant collagen gels. In the absence of proteolysis, tumor cells embedded in extracellular matrices were trapped in a compact, spherical configuration and were unable to undergo changes in cell shape or cytoskeletal reorganization required for 3-dimensional growth.
In a proband with Winchester syndrome (WNCHRS; 277950), originally described by Winchester et al. (1969), Evans et al. (2012) identified a homozygous missense mutation in the MMP14 gene (600754.0001). The mutation, which occurred in the hydrophobic region of the signal peptide, decreased MMP14 membrane localization with consequent impairment of pro-MMP2 activation.
In 2 Dutch brothers with Winchester syndrome, de Vos et al. (2018) identified homozygosity for a missense mutation in the MMP14 gene (R111H; 600754.0002). Their unaffected first-cousin parents and unaffected sister were heterozygous for the mutation. Functional analysis indicated that the R111H mutant exerts some residual activity, but at a significantly reduced level.
By gene targeting, Holmbeck et al. (1999) generated mice deficient in the Mmp14 gene, which they called MT1-MMP. Mmp14 deficiency caused craniofacial dysmorphism, arthritis, osteopenia, dwarfism, and fibrosis of soft tissues due to ablation of a collagenolytic activity that is essential for modeling of skeletal and extraskeletal connective tissues. These findings demonstrated the pivotal function of MMP14 in connective tissue metabolism and illustrated that modeling of the soft connective tissue matrix by resident cells is essential for the development and maintenance of the hard tissues of the skeleton.
The MMP family, which has approximately 25 members in mammals, has been implicated in extracellular matrix remodeling associated with embryonic development, cancer formation and progression, and various other physiologic and pathologic events. Oh et al. (2004) stated that at the time of their report, inactivating mutations in individual matrix metalloproteinase genes in mice were nonlethal, at least for the first few weeks after birth, suggesting functional redundancy among MMP family members. The authors reported that mice lacking 2 MMPs, a nonmembrane type (MMP2; 120360) and a membrane type (MT1-MMP), die immediately after birth with respiratory failure, abnormal blood vessels, and immature muscle fibers reminiscent of central core disease (117000). In the absence of Mmp2 and MT1-MMP, myoblast fusion in vitro was also significantly retarded. These findings suggested functional overlap in mice between the 2 MMPs with distinct molecular natures. Mutations in both were synthetically lethal in mice.
Chun et al. (2006) showed that Mt1-mmp coordinated adipocyte differentiation in mice. In the absence of Mt1-mmp, white adipose tissue development was aborted, leaving tissues populated by mini-adipocytes that rendered null mice lipodystrophic. Null preadipocytes were able to differentiate into functional adipocytes in a 2-dimensional culture, but not in a 3-dimensional gel.
Sakr et al. (2018) reported that the N-ethyl-N-nitrosourea (ENU)-generated 'cartoon' mouse mutant exhibited profound growth and developmental defects similar to those of Mt1-mmp -/- mice. Moreover, fibroblasts of both Mt1-mmp -/- mice and cartoon mice lost pericellular collagenolytic activity. The authors reported that cartoon mice harbored a ser466-to-pro (S466P) mutation in the hemopexin domain of Mt1-mmp. Mt1-mmp with the S466P mutation lost hemopexin-dependent Mt1-mmp activity, exhibited multiple defects in proteolytic processing, and did not undergo trafficking to cell surface to function as a pericellular proteinase. In contrast, a hemopexin-deleted Mt-mmp mutant retained proteolytic function and activity, indicating that the hemopexin domain did not play a required role in regulating Mt-mmp proteolytic or functional activity. Examination of the crystal structure of the Mt1-mmp hemopexin domain revealed that the S466P mutation induced structural changes in the domain. Further analyses demonstrated that S466P was a temperature-sensitive mutation that caused failure of Mt1-mmp to undergo proprotein convertase-dependent processing, disrupting its intracellular trafficking and confining it in the endoplasmic reticulum.
De Vos et al. (2018) performed functional analysis of the S466P mutant and observed a pronounced effect on protein processing and trafficking, but only reduced activity in gelatin zymography and nearly normal activity in the gelatin invadopodia assay. The mutation also did not affect the ability of MMP14 to support cellular migration. The authors noted that it was difficult to reconcile the severe Cartoon phenotype, which so strongly resembles that of a full Mmp14 knockout, with the observed near-normal activity of the S466P mutant. They suggested that S466P might affect functionality of other cell types, such as macrophages and osteoblasts, to a greater extent than that of fibroblasts. De Vos et al. (2018) also generated mmp14a/b knockout (KO) zebrafish and observed recapitulation of key aspects of Winchester syndrome (277950). The KO fish exhibited decreased total body length, relatively small head with dorsal hyperextension, exophthalmos, short operculum, and thoracic hyperkyphosis. The mutants had a shortened average life span and failed to reproduce. Microcomputed tomography showed significantly reduced skull bone mineral density and Weberian-prehemal hyperkyphosis. Early in development, KO larvae developed normal craniofacial cartilage elements, and subsequent mineralization of the larval skeleton during metamorphosis proceeded normally as well, with the first subtle differences in skull shape only becoming apparent at juvenile age. The authors noted that the gradually worsening phenotype observed in MMP14-mutated humans, mice, and zebrafish suggested that loss of MMP14 disrupts later stages of skeletal remodeling and argued against a major role for MMP14 supporting cellular migratory or invasive behavior in vivo.
In a proband with Winchester syndrome (WNCHRS; 277950), originally described by Winchester et al. (1969), Evans et al. (2012) identified a homozygous 284C-G transversion in the MMP14 gene, resulting in a thr17-to-arg (T17R) substitution. The mutation, which occurred in the hydrophobic region of the signal peptide, decreased MMP14 membrane localization with consequent impairment of pro-MMP2 activation. The mutation was not present in the dbSNP (build 132) or 1000 Genomes Project databases or in 100 Puerto Rican control chromosomes.
De Vos et al. (2018) studied MMP14 processing and subcellular localization in MRC5 cells and observed impaired signal-sequence removal and cell surface localization with the T17R mutant compared to wildtype MMP14. Using gelatin zymography, the authors demonstrated that the T17R mutant abrogates pro-MMP2 processing, whereas wildtype MMP14 converts pro-MMP2 to its intermediate and active forms. In addition, cells expressing the T17R mutant showed significantly reduced migratory behavior on a fibronectin substrate.
In 2 Dutch brothers with a mild form of Winchester syndrome (WNCHRS; 277950), originally described by van Steensel et al. (2007), de Vos et al. (2018) identified homozygosity for a c.332G-A transition in the MMP14 gene, resulting in an arg111-to-his (R111H) substitution within the PRO domain. Their unaffected first-cousin parents and an unaffected sister were heterozygous for the mutation. Functional analysis using gelatin zymography showed reduced pro-MMP2 processing with the R111H mutant compared to wildtype MMP14, although the mutant protein retained partial activity. Gelatin invadopodia assay confirmed the zymography data, showing a significant reduction in gelatin degradation with the R111H mutant, although it retained partial activity. In addition, cells expressing the R111H mutant showed significantly reduced migratory behavior on a fibronectin substrate.
Chun, T.-H., Hotary, K. B., Sabeh, F., Saltiel, A. R., Allen, E. D., Weiss, S. J. A pericellular collagenase directs the 3-dimensional development of white adipose tissue. Cell 125: 577-591, 2006. [PubMed: 16678100] [Full Text: https://doi.org/10.1016/j.cell.2006.02.050]
de Vos, I. J. H. M., Tao, E. Y., Ong, S. L. M., Goggi, J. L., Scerri, T., Wilson, G. R., Low, C. G. M., Wong, A. S. W., Grussu, D., Stegmann, A. P. A., van Geel, M., Janssen, R., Amor, D. J., Bahlo, M., Dunn, N. R., Carney, T. J., Lockhart, P. J., Coull, B. J., van Steensel, M. A. M. Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype. Hum. Molec. Genet. 27: 2775-2788, 2018. [PubMed: 29741626] [Full Text: https://doi.org/10.1093/hmg/ddy168]
Evans, B. R., Mosig, R. A., Lobl, M., Martignetti, C. R., Camacho, C., Grum-Tokars, V., Glucksman, M. J., Martignetti, J. A. Mutation of membrane type-1 metalloproteinase, MT1-MMP, causes the multicentric osteolysis and arthritis disease Winchester syndrome. Am. J. Hum. Genet. 91: 572-576, 2012. [PubMed: 22922033] [Full Text: https://doi.org/10.1016/j.ajhg.2012.07.022]
Holmbeck, K., Bianco, P., Caterina, J., Yamada, S., Kromer, M., Kuznetsov, S. A., Mankani, M., Robey, P. G., Poole, A. R., Pidoux, I., Ward, J. M., Birkedal-Hansen, H. MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 99: 81-92, 1999. [PubMed: 10520996] [Full Text: https://doi.org/10.1016/s0092-8674(00)80064-1]
Hotary, K. B., Allen, E. D., Brooks, P. C., Datta, N. S., Long, M. W., Weiss, S. J. Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Cell 114: 33-45, 2003. [PubMed: 12859896] [Full Text: https://doi.org/10.1016/s0092-8674(03)00513-0]
Mignon, C., Okada, A., Mattei, M. G., Basset, P. Assignment of the human membrane-type matrix metalloproteinase (MMP14) gene to 14q11-q12 by in situ hybridization. Genomics 28: 360-361, 1995. [PubMed: 8530054] [Full Text: https://doi.org/10.1006/geno.1995.1159]
Noda, K., Ishida, S., Inoue, M., Obata, K., Oguchi, Y., Okada, Y., Ikeda, E. Production and activation of matrix metalloproteinase-2 in proliferative diabetic retinopathy. Invest. Ophthal. Vis. Sci. 44: 2163-2170, 2003. [PubMed: 12714657] [Full Text: https://doi.org/10.1167/iovs.02-0662]
Oh, J., Takahashi, R., Adachi, E., Kondo, S., Kuratomi, S., Noma, A., Alexander, D. B., Motoda, H., Okada, A., Seiki, M., Itoh, T., Itohara, S., Takahashi, C., Noda, M. Mutations in two matrix metalloproteinase genes, MMP-2, and MT1-MMP, are synthetic lethal in mice. Oncogene 23: 5041-5048, 2004. [PubMed: 15064723] [Full Text: https://doi.org/10.1038/sj.onc.1207688]
Sakr, M., Li, X., Sabeh, F., Feinberg, T. Y., Tesmer, J. J. G., Tang, Y., Weiss, S. J. Tracking the Cartoon mouse phenotype: hemopexin domain-dependent regulation of MT1-MMP pericellular collagenolytic activity. J. Biol. Chem. 293: 8113-8127, 2018. [PubMed: 29643184] [Full Text: https://doi.org/10.1074/jbc.RA117.001503]
Sato, H., Takino, T., Okada, Y., Cao, J., Shinagawa, A., Yamamoto, E., Seiki, M. A matrix metalloproteinase expressed on the surface of invasive tumor cells. Nature 370: 61-65, 1994. [PubMed: 8015608] [Full Text: https://doi.org/10.1038/370061a0]
Takino, T., Sato, H., Yamamoto, E., Seiki, M. Cloning of a human gene potentially encoding a novel matrix metalloproteinase having a C-terminal transmembrane domain. Gene 155: 293-298, 1995. [PubMed: 7721107] [Full Text: https://doi.org/10.1016/0378-1119(94)00637-8]
Ueda, M., Yamashita, Y., Takehara, M., Terai, Y., Kumagai, K., Ueki, K., Kanda, K., Yamaguchi, H., Akise, D., Hung, Y.-C., Ueki, M. Survivin gene expression in endometriosis. J. Clin. Endocr. Metab. 87: 3452-3459, 2002. [PubMed: 12107265] [Full Text: https://doi.org/10.1210/jcem.87.7.8682]
van Steensel, M. A. M., Ceulen, R. P. M., Delhaas, T., de Die-Smulders, C. Two Dutch brothers with Borrone dermato-cardio-skeletal syndrome. Am. J. Med. Genet. 143A: 1223-1226, 2007. [PubMed: 17480005] [Full Text: https://doi.org/10.1002/ajmg.a.31719]
Winchester, P., Grossman, H., Lim, W. N., Danes, B. S. A new acid mucopolysaccharidosis with skeletal deformities simulating rheumatoid arthritis. Am. J. Roentgen. Radium Ther. Nucl. Med. 106: 121-128, 1969. [PubMed: 4238825] [Full Text: https://doi.org/10.2214/ajr.106.1.121]