Alternative titles; symbols
HGNC Approved Gene Symbol: TIMP1
Cytogenetic location: Xp11.3 Genomic coordinates (GRCh38) : X:47,582,436-47,586,789 (from NCBI)
Although erythropoietin (133170) is the primary physiologic regulator of erythropoiesis, in vitro studies identified another class of mediators important in stimulating erythroid progenitors. Gasson et al. (1985) isolated a cDNA molecular clone encoding a 28,000 MW glycoprotein of this class, called erythroid-potentiating activity.
The nucleotide sequence of the gene for human tissue inhibitor of metalloproteinase (TIMP) is identical to that of EPA (Docherty et al., 1985).
TIMP is identical to the collagenase inhibitor. Human collagenase inhibitor (HCI) appears to play a major role in modulating the activity of interstitial collagenase as well as a number of connective tissue metalloendoproteases. HCI functions through the formation of a tight 1:1 complex with active collagenase. HCI has been identified as a secretory product of platelets and alveolar macrophages. Carmichael et al. (1986) described the primary structure of HCI secreted by fibroblasts and the isolation and sequencing of the corresponding cDNA.
Gasson et al. (1985) observed that the EPA gene appears to be encoded by a single gene that is about 3 kb long and is interrupted by at least 2 introns.
Derry and Barnard (1991) demonstrated that the TIMP gene lies within an intron of the synapsin I gene (SYN1; 313440) in both man and mouse. The TIMP gene is transcribed in the opposite direction to the SYN1 gene in the mouse and presumably in man. Specifically, Derry and Barnard (1992) demonstrated that the TIMP gene lies within intron 6 of the SYN1 gene, which has 13 exons. The ARAF gene (311010), which is transcribed in the same direction as TIMP, is situated 10 kb away.
Huebner et al. (1986) assigned the EPA gene to the X chromosome by analysis of its segregation pattern in mouse-human somatic cell hybrids using a cDNA clone. A genomic clone was used to regionalize the EPA locus by in situ hybridization. It was found to reside at Xp11.4-p11.1. This is the first growth factor found to be X-linked. Jackson et al. (1987) used a cross between 2 mouse species (with different EcoRI restriction fragments of the TIMP locus) to demonstrate that the locus is X-linked in the mouse also.
Collagenase and related metalloproteinases are responsible for much of the remodeling that occurs in connective tissue. The extracellular activity of these enzymes may be regulated by TIMP. Spurr et al. (1987) assigned the TIMP gene to Xp11.4-p11.1 by probing DNA from somatic cell hybrids with a variety of rearranged X chromosomes. Two patients with Norrie disease (310600) and a submicroscopic deletion of Xp11.3, reported by Gal et al. (1986), were found to retain the TIMP gene. Thus, TIMP is not closely linked to Norrie disease.
Using a series of somatic cell hybrids segregating translocation and deletion X chromosomes, Willard et al. (1989) mapped the TIMP locus to Xp11.4-p11.23. By linkage analysis, TIMP was found to be located about 22 cM proximal to OTC (300461).
Kenney et al. (2005) found that keratoconus (see 148300) corneas exhibited a 1.8-fold decrease in TIMP1 mRNA and a 2.8-fold decrease in protein compared with normal (physiologic) corneas. Additionally, they found a 2.20-fold increase in catalase (115500) mRNA and 1.8-fold increase in enzyme activity, and a 1.5-fold increase in cathepsis V/L2 (603308) mRNA and abnormal protein distribution. Kenney et al. (2005) concluded that keratoconus corneas had elevated levels of cathepsins V/L2, B (116810), and G (116830), which could stimulate hydrogen peroxide production, which, in turn, could upregulate catalase, an antioxidant enzyme. In addition, decreased TIMP1 and increased cathepsin V/L2 levels might play a role in the matrix degradation that is a hallmark of keratoconus corneas. These findings supported the hypothesis that keratoconus corneas undergo oxidative stress and tissue degradation.
Because matrix degrading enzymes could potentially influence keratoconus progression, Matthews et al. (2007) studied the effects of TIMP1 and TIMP3 (188826) on stromal cell viability. Overexpression of TIMP3 induced apoptosis in corneal stromal cell cultures. Upregulated TIMP1 production or the addition of exogenous TIMP1 protein prevented stromal cell overgrowth, changed stromal cell morphology, and reduced the extent of TIMP3 induced apoptosis. Localized relative concentrations of TIMP1/TIMP3 could thus determine whether cells remained viable or became apoptotic. Matthews et al. (2007) concluded that this might be relevant to keratoconus because significantly more apoptotic cells were identified in the anterior stroma of keratoconic corneas than in normal corneas and the majority of the TIMP1 and TIMP3 producing stromal cells were located in that region.
X Inactivation Studies
Brown et al. (1990) described a method for using hybrids under positive selection for the retention of either the active or inactive human X chromosome to analyze the transcriptional activity of the human TIMP gene compared with that of the human MIC2 gene (313470), which is known to escape X inactivation. Using Northern blot analysis, they detected both MIC2 and TIMP transcripts in the hybrids containing an active X, but only MIC2 transcripts in the hybrids with an inactive X. Further analysis of the RNA from these hybrids by polymerase chain reaction (PCR) amplification demonstrated that transcription of the TIMP gene on the inactive X chromosome is repressed by a factor of at least 100-fold compared to transcription from the active X chromosome. Since TIMP maps to the same region as another gene, A1S9T (314370), which is known not to be inactivated, the question of inactivation of TIMP was a valid one.
X inactivation silences most, but not all, of the genes on 1 of the 2 X chromosomes in mammalian females. The human X chromosome preserves its activation status when isolated in rodent/human somatic cell hybrids, and hybrids retaining either the active or inactive X chromosome have been used to assess the inactivation status of many X-linked genes. The TIMP1 gene is expressed in some, but not all, inactive X-containing somatic cell hybrids, suggesting that this gene is either prone to reactivation or variable in its inactivation. Since many genes that escape X inactivation are clustered, Anderson and Brown (1999) examined the expression of 4 genes within approximately 100 kb of TIMP1: ARAF1 (311010), ELK1 (311040), ZNF41 (314995), and ZNF157 (300024). All 4 genes were expressed only from the active X chromosome, demonstrating that the factors allowing TIMP1 expression from the inactive X chromosome are specific to the TIMP1 gene. To determine if this variable inactivation of TIMP1 is a function of the hybrid-cell environment or also is observed in human cells, Anderson and Brown (1999) developed an allele-specific assay to assess TIMP1 expression in human females. Expression of 2 alleles was detected in some female cells with previously demonstrated extreme skewing of X inactivation, indicating TIMP1 expression from the inactive X chromosome. However, in other cells, no expression of TIMP1 was observed from the inactive X chromosome, suggesting that TIMP1 inactivation is polymorphic in human females.
To identify genes that escape X inactivation and to generate a first-generation X-inactivation profile of the X chromosome, Carrel et al. (1999) evaluated the expression of 224 X-linked genes and expressed sequence tags by RT-PCR analysis of a panel of multiple independent mouse/human somatic cell hybrids containing a normal inactivated X but no active X. Of the 224 transcripts tested, 177 appeared to be subject to inactivation, whereas 34 (3 of which were pseudoautosomal) escaped inactivation. The status of only 13 genes (6%) was indeterminate, because they were expressed in about half of the hybrids tested. Such heterogeneous patterns may reflect a naturally occurring heterogeneity in human cells (as demonstrated for TIMP1 by Anderson and Brown, 1999), occasional reactivation of human X-linked genes in somatic cell hybrids, and/or an innately unstable epigenetic state.
In a study of X-linked progressive retinal atrophy in the Siberian Husky dog, Zeiss et al. (1998) found no sequence difference in the TIMP1 coding region of affected and unaffected dogs and excluded TIMP1 by linkage studies using an intragenic polymorphism. However, they found that TIMP1 is overexpressed in affected dogs several months before retinal degeneration is histologically evident, implying that alterations in interphotoreceptor matrix composition precede retinal degeneration by a significant time period.
Anderson, C. L., Brown, C. J. Polymorphic X-chromosome inactivation of the human TIMP1 gene. Am. J. Hum. Genet. 65: 699-708, 1999. [PubMed: 10441576] [Full Text: https://doi.org/10.1086/302556]
Brown, C. J., Flenniken, A. M., Williams, B. R. G., Willard, H. F. X chromosome inactivation of the human TIMP gene. Nucleic Acids Res. 18: 4191-4195, 1990. [PubMed: 2377460] [Full Text: https://doi.org/10.1093/nar/18.14.4191]
Carmichael, D. F., Sommer, A., Thompson, R. C., Anderson, D. C., Smith, C. G., Welgus, H. G., Stricklin, G. P. Primary structure and cDNA cloning of human fibroblast collagenase inhibitor. Proc. Nat. Acad. Sci. 83: 2407-2411, 1986. [PubMed: 3010309] [Full Text: https://doi.org/10.1073/pnas.83.8.2407]
Carrel, L., Cottle, A. A., Goglin, K. C., Willard, H. F. A first-generation X-inactivation profile of the human X chromosome. Proc. Nat. Acad. Sci. 96: 14440-14444, 1999. [PubMed: 10588724] [Full Text: https://doi.org/10.1073/pnas.96.25.14440]
Derry, J. M., Barnard, P. J. The gene for tissue inhibitor of metalloproteinases (TIMP) is located within an intron of the synapsin I gene on the X chromosome. (Abstract) Cytogenet. Cell Genet. 58: 2061-2062, 1991.
Derry, J. M. J., Barnard, P. J. Physical linkage of the A-raf-1, properdin, synapsin I, and TIMP genes on the human and mouse X chromosomes. Genomics 12: 632-638, 1992. [PubMed: 1572636] [Full Text: https://doi.org/10.1016/0888-7543(92)90286-2]
Docherty, A. J. P., Lyons, A., Smith, B. J., Wright, E. M., Stephens, P. E., Harris, T. J. R. Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity. Nature 318: 66-69, 1985. [PubMed: 3903517] [Full Text: https://doi.org/10.1038/318066a0]
Gal, A., Wieringa, B., Smeets, D. F. C. M., Bleeker-Wagemakers, L., Ropers, H. H. Submicroscopic interstitial deletion of the X chromosome explains a complex genetic syndrome dominated by Norrie disease. Cytogenet. Cell Genet. 42: 219-224, 1986. [PubMed: 3502689] [Full Text: https://doi.org/10.1159/000132282]
Gasson, J. C., Golde, D. W., Kaufman, S. E., Westbrook, C. A., Hewick, R. M., Kaufman, R. J., Wong, G. G., Temple, P. A., Leary, A. C., Brown, E. L., Orr, E. C., Clark, S. C. Molecular characterization and expression of the gene encoding human erythroid-potentiating activity. Nature 315: 768-771, 1985. [PubMed: 3839290] [Full Text: https://doi.org/10.1038/315768a0]
Huebner, K., Isobe, M., Gasson, J. C., Golde, D. W., Croce, C. M. Localization of the gene encoding human erythroid-potentiating activity to chromosome region Xp11.1-Xp11.4. Am. J. Hum. Genet. 38: 819-826, 1986. [PubMed: 3460333]
Jackson, I. J., LeCras, T. D., Docherty, A. J. P. Assignment of the TIMP gene to the murine X-chromosome using an inter-species cross. Nucleic Acids Res. 15: 4357 only, 1987. [PubMed: 3588297] [Full Text: https://doi.org/10.1093/nar/15.10.4357]
Kenney, M. C., Chwa, M., Atilano, S. R., Tran, A., Carballo, M., Saghizadeh, M., Vasiliou, V., Adachi, W., Brown, D. J. Increased levels of catalase and cathepsin V/L2 but decreased TIMP-1 in keratoconus corneas: evidence that oxidative stress plays an role in this disorder. Invest. Ophthal. Vis. Sci. 46: 823-832, 2005. [PubMed: 15728537] [Full Text: https://doi.org/10.1167/iovs.04-0549]
Matthews, F. J., Cook, S. D., Majid, M. A., Dick, A. D., Smith, V. A. Changes in the balance of the tissue inhibitor of matrix metalloproteinases (TIMPs)-1 and -3 may promote keratocyte apoptosis in keratoconus. Exp. Eye Res. 84: 1125-1134, 2007. [PubMed: 17449031] [Full Text: https://doi.org/10.1016/j.exer.2007.02.013]
Spurr, N. K., Goodfellow, P. N., Docherty, A. J. P. Chromosomal assignment of the gene encoding the human tissue inhibitor of metalloproteinases to Xp11.1-p11.4. Ann. Hum. Genet. 51: 189-194, 1987. [PubMed: 3688834] [Full Text: https://doi.org/10.1111/j.1469-1809.1987.tb00870.x]
Willard, H. F., Durfy, S. J., Mahtani, M. M., Dorkins, H., Davies, K. E., Williams, B. R. G. Regional localization of the TIMP gene on the human X chromosome: extension of a conserved synteny and linkage group on proximal Xp. Hum. Genet. 81: 234-238, 1989. [PubMed: 2921031] [Full Text: https://doi.org/10.1007/BF00278995]
Zeiss, C. J., Acland, G. M., Aguirre, G. D., Ray, K. TIMP-1 expression is increased in X-linked progressive retinal atrophy despite its exclusion as a candidate gene. Gene 225: 67-75, 1998. [PubMed: 9931441] [Full Text: https://doi.org/10.1016/s0378-1119(98)00521-6]