HGNC Approved Gene Symbol: TIMP3
SNOMEDCT: 193410003;
Cytogenetic location: 22q12.3 Genomic coordinates (GRCh38): 22:32,801,705-32,863,041 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q12.3 | Sorsby fundus dystrophy | 136900 | Autosomal dominant | 3 |
The tissue inhibitors of metalloproteinases (TIMPs) are natural inhibitors of the matrix metalloproteinases, a group of zinc-binding endopeptidases involved in the degradation of the extracellular matrix. Apte et al. (1994) isolated overlapping cDNAs encoding a novel member of the group, TIMP3. The cDNAs contained a 591-bp open reading frame encoding 9 amino acid residues of the signal peptide and 188 residues of the mature TIMP3 polypeptide. Both the nucleotide sequence and the deduced translation product of the TIMP3 cDNA had a high degree of similarity to the TIMP1 (305370) and TIMP2 (188825) gene products, including 12 conserved cysteinyl residues at the same relative positions. The TIMP3 gene is expressed in many tissues, with highest expression in the placenta.
Wilde et al. (1994) cloned and sequenced TIMP3 from phorbol ester-differentiated cells stimulated with bacterial lipopolysaccharide. The open reading frame encoded a 211-amino acid precursor, including a 23-residue secretion signal. The mature polypeptide had a calculated molecular weight of 21.6 kD.
Osman et al. (2002) showed that mature dendritic cells (DCs) produce more MMP9 (120361) than do immature DCs, facilitating their hydroxaminic acid-inhibitable migration through gel in vitro and, presumably, through the extracellular matrix to monitor the antigenic environment in vivo. RT-PCR analysis indicated that the enhanced expression of MMP9 is correlated with a downregulation of TIMP1 and, particularly, TIMP2, while expression of TIMP3 is upregulated. The authors concluded that the balance of MMP and TIMP determines the net migratory capacity of DCs. They proposed that TIMP3 may be a marker for mature DCs.
TIMP3 encodes a potent angiogenesis inhibitor and is mutated in Sorsby fundus dystrophy (136900), a macular degenerative disease with submacular choroidal neovascularization. Qi et al. (2003) demonstrated the ability of TIMP3 to inhibit VEGF (192240)-mediated angiogenesis and identified the potential mechanism by which this occurs: TIMP3 blocks the binding of VEGF to VEGFR2 (191306) and inhibits downstream signaling and angiogenesis. This property seems to be independent of its MMP-inhibitory activity, indicating a new function for TIMP3.
Wild et al. (2003) studied molecular mechanisms contributing to the tumorigenesis of pancreatic endocrine tumors (PETs). Allelic deletions at chromosome 22q12.3 were detected in about 30 to 60% of PETs, suggesting that inactivation of one or more tumor suppressor genes on this chromosomal arm is important for their pathogenesis. Because the putative tumor suppressor gene TIMP3 has been located at 22q12.3, Wild et al. (2003) undertook a genetic analysis of TIMP3 to determine its role in the tumorigenesis of PETs. Thirteen of 21 PETs (62%) revealed TIMP3 alterations, including promoter hypermethylation and homozygous deletion. The predominant TIMP3 alteration was promoter hypermethylation, identified in 8 of 18 PETs (44%). It was tumor-specific and corresponded to loss or strong reduction of TIMP3 protein expression. Notably, 11 of 14 PETs (79%) with metastases had TIMP3 alterations, compared with only 1 of 7 PETs (14%) without metastases (P less than 0.02). These data suggested a possibly important role of TIMP3 in the tumorigenesis of human PETs, especially in the development of metastases.
Because matrix degrading enzymes could potentially influence keratoconus (see 148300) progression, Matthews et al. (2007) studied the effects of TIMP1 and TIMP3 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.
Stohr et al. (1995) reported the genomic organization of the TIMP3 gene. TIMP3 is encoded by 5 exons extending over approximately 55 kb of genomic DNA. The authors compared the 5-prime flanking sequences of the human and mouse TIMP3 genes and found a high degree of similarity between them.
By hybridization to a panel of human/hamster somatic cell hybrid DNAs, Apte et al. (1994) mapped the TIMP3 gene to chromosome 22; by in situ hybridization, they regionalized the assignment to 22q12.1-q13.2. By analysis of a panel of mouse/human hybrids, Wilde et al. (1994) assigned the gene to chromosome 22.
Overlapping gene groups (OGGs) arise when exons of 1 gene are contained within the introns of another. Typically, the 2 overlapping genes are encoded on opposite DNA strands. Karlin et al. (2002) identified genes with OGG architecture and examined their relation to disease. OGGs appear to be susceptible to genomic rearrangement, as happens commonly with the loci of DiGeorge syndrome (188400) on chromosome 22. Karlin et al. (2002) also examined the degree of conservation of OGGs between human and mouse and cited the striking example of the TIMP and synapsin genes in the 2 species: TIMP3 and SYN3 (602705) are on human chromosome 22q12.3 and mouse chromosome 10; TIMP1 and SYN1 (313440) are on human Xp11.3-p11.2 and the mouse X chromosome; and SYN2 (600755) and TIMP4 are on human 3p25 and mouse chromosome 6.
Weber et al. (1994), who had mapped the gene for Sorsby fundus dystrophy (SFD; 1136900) to 22q13-qter, examined the TIMP3 gene as a possible site of causative mutations in SFD on the basis of its chromosomal location and its pivotal role in extracellular matrix remodeling. They identified point mutations in TIMP3 in affected members of 2 SFD pedigrees. These mutations were predicted to disrupt the tertiary structure and thus the functional properties of the mature protein.
Langton et al. (1998) found that wildtype TIMP3 is localized entirely to the extracellular matrix (ECM) in both its glycosylated (27 kD) and unglycosylated (24 kD) forms. A COOH-terminally truncated TIMP3 molecule was found to be a non-ECM-bound matrix metalloproteinase (MMP) inhibitor, whereas a chimeric TIMP molecule, consisting of the NH2-terminal domain of TIMP2 fused to the COOH-terminal domain of TIMP3, displayed ECM binding, albeit with a lower affinity than the wildtype TIMP3 molecule. Thus, as in TIMP1 and TIMP2, the NH2-terminal domain is responsible for MMP inhibition, whereas the COOH-terminal domain is most important in mediating the specific functions of the molecule. A mutant TIMP3 in which serine-181 was changed to cysteine (S181C; 188826.0001), found in Sorsby fundus dystrophy, gave rise to an additional 48-kD species (possibly a TIMP3 dimer) that retained its ability to inhibit MMPs and localize to the ECM when expressed in COS-7 cells. These data favored the hypothesis that the TIMP3 mutation seen in Sorsby fundus dystrophy contributes to disease progression by accumulation of mutant protein rather than by loss of functional TIMP3.
Ayyagari et al. (2000) described a 4-generation pedigree with autosomal dominant hemorrhagic macular degeneration. The phenotype overlapped that of Sorsby fundus dystrophy. Despite the phenotypic similarities to Sorsby fundus dystrophy, the large kindred studied by these authors showed no involvement of the TIMP3 gene by linkage, haplotype, or mutation analysis. They concluded that exclusion of the TIMP3 gene in this family indicates genetic heterogeneity for autosomal dominant hemorrhagic macular dystrophy. The authors reviewed the mutations reported in all Sorsby fundus dystrophy pedigrees to that time: all families in the literature showed mutations in the TIMP3 gene, all involving exon 5 or the intron 4/exon 5 junction.
Langton et al. (2000) stated that 5 different mutations in the TIMP3 gene had previously been identified in cases of Sorsby fundus dystrophy, all introducing an extra cysteine residue into exon 5 (which forms part of the C-terminal domain) of the TIMP3 molecule. They described the expression of several of these mutated genes and reported a novel TIMP3 mutation in a family with Sorsby fundus dystrophy that resulted in truncation of most of the C-terminal domain of the molecule (E139X; 188826.0005). Despite these differences, all of these molecules were expressed and exhibited characteristics of the normal protein, including inhibition of metalloproteinases and binding to the extracellular matrix. However, unlike wildtype TIMP3, they all formed dimers. These observations, together with the finding that expression of the TIMP3 gene is increased, rather than decreased, in eyes from patients with SFD, provided evidence that dimerized TIMP3 plays an active role in the disease process by accumulating in the eye. Increased expression of TIMP3 is observed in other degenerative retinal diseases, including the more severe forms of age-related macular degeneration.
Langton et al. (2005) expressed a range of SFD mutants from human retinal pigment epithelial (RPE) cells, including S181C, S156C (188826.0003), and E139X. Resistance to turnover, resulting from intermolecular disulfide bond formation, was a common property of all the SFD mutants examined, providing a possible explanation for the increased deposition of the protein observed in eyes from SFD patients. In contrast, SFD mutants varied in their ability to inhibit cell-surface activation of MMP2 (120360), a potent mediator of angiogenesis, ranging from being fully active to totally inactive. Langton et al. (2005) concluded that increased deposition of active TIMP3, rather than dysregulation of metalloproteinase inhibition, is likely to be the primary initiating event in SFD.
Mohammed et al. (2004) showed that deletion of the mouse gene Timp3 resulted in an increase in the activity of TNF-alpha converting enzyme (TACE; 603639), constitutive release of TNF (191160), and activation of TNF signaling in the liver. The increase in TNF in Timp3 -/- mice culminated in hepatic lymphocyte infiltration and necrosis, features that are also seen in chronic active hepatitis in humans. This pathology was prevented when deletion of Timp3 was combined with deficiency of tumor necrosis factor receptor superfamily, member 1a (TNFRSF1A; 191190). In a liver regeneration model that required TNF signaling, Timp3 -/- mice succumbed to liver failure. Hepatocytes from the null mice completed the cell cycle but then underwent cell death owing to sustained activation of TNF. This hepatocyte cell death was completely rescued by a neutralizing antibody to TNF. Dysregulation of TNF occurred specifically in Timp3 -/- mice and not in mice null for the Timp1 gene (305370). These data indicated that TIMP3 is a crucial innate negative regulator of TNF in both tissue homeostasis and tissue response to injury.
In affected members of a family with Sorsby fundus dystrophy (SFD; 136900), Weber et al. (1994) found an SSCP band shift in exon 5 of the TIMP3 gene and showed that it was caused by an A-to-T transversion, changing a conserved serine residue to a cysteine at position 181 (S181C). This transversion event also created a new NsiI restriction site which they used to demonstrate segregation of the mutation in the 12 affected members of the pedigree.
Carrero-Valenzuela et al. (1996) reported a family with SFD associated with the S181C mutation in TIMP3. The proband was a 44-year-old white woman who was initially evaluated at the age of 33 because of nyctalopia. Drusen-like changes were present in both eyes, the results of dark adaptometry were profoundly abnormal, and the electroretinogram and electrooculogram showed mild impairment. She developed choroidal neovascularization in her left eye at age 37 and in her right eye at age 39. Despite multiple sessions of laser photocoagulation, her visual acuity declined to 20/400 OU owing to foveal recurrence and disciform macular scarring. Four living relatives had bilateral exudative maculopathy and legal blindness before age 50. Three other relatives were probably affected; 2 had clinical reports of early-onset disciform maculopathy and central vision loss, and 1 had onset of visual symptoms at age 55 with documented disciform macular scars at age 66. Two or 3 other members of the family may have been affected as well.
A total of 15 families segregating Sorsby fundus dystrophy, unrelated on the basis of genealogy, were identified by Wijesuriya et al. (1996) from a large database of genetic eye disease families originating from diverse parts of the British Isles. In each family the identification of the ser181-to-cys mutation segregating with the disease suggested a founder effect. In all families studied, the same relatively infrequent allele (occurring in just 11% of the control group) was associated with disease at marker locus D22S280. A highly significant disease-associated haplotype, spanning 3 cM of the TIMP3 locus, was conserved in 11 of the 15 families (68% of affected chromosomes); a further extended haplotype spanning up to 7 cM was identified in 5 families (27% of Sorsby-associated chromosomes) and possibly represented the ancestral haplotype. This haplotype analysis refined the TIMP3 gene localization to a 1- to 3-cM interval between D22S273 and D22S281 and provided strong evidence for a single mutational event being responsible for most Sorsby fundus dystrophy in the British Isles where the disorder was first described.
In 2 brothers with Sorsby fundus dystrophy (SFD; 136900), Weber et al. (1994) found a heterozygous A-to-G transition in the TIMP3 gene, changing codon 168 from a highly conserved tyrosine residue to cysteine.
In a German-Czech family in which at least 12 members had Sorsby fundus dystrophy (136900), Felbor et al. (1995) demonstrated heterozygosity for a C-to-G transversion in the second position of codon 156 of the TIMP3 gene, leading to the replacement of a conserved serine residue by a cysteine. At the onset of the disease, a central subretinal neovascularization occurred followed by extensive scarring. Corresponding to the morphologic changes a central scotoma was found. However, in contrast to previous descriptions, symptoms were observed approximately 10 to 15 years earlier with a mean age at onset of 25 years. The disease then progressed more rapidly, with a second eye involvement occurring within months. In the course of several years, the patients developed tapetal retinal dystrophy with intraretinal perivascular bone spicular pigment proliferation, attenuation of the intraretinal arteries, and atrophy of the choriocapillaris. These changes were accompanied by loss of the peripheral visual field, decrease in dark adaptation, and subnormal scotopic and photopic ERG. All 3 mutations described at the time of the Felbor et al. (1995) report occurred in the COOH-terminal part of the mature TIMP3 protein within 25 amino acids from each other. The additional thiol group in each case is located close to the last 2 conserved cysteine residues which normally participate in intrachain disulfide bond arrangements.
In a large family residing in the isolated parish of Lavia in southwestern Finland, in which several members had Sorsby fundus dystrophy (136900), a possible autosomal recessive form of SFD was proposed by Forsius et al. (1982). However, molecular genetic studies by Felbor et al. (1997) indicated that all affected individuals were in fact heterozygous for a gly166-to-cys mutation in TIMP3, thus providing strong evidence for autosomal dominant inheritance of the SFD phenotype. In this kindred, a consanguineous couple and all of their 8 children had been found to be affected, suggesting recessive inheritance. A follow-up study demonstrated an affected mother and daughter elsewhere in the pedigree.
In affected members of a family with Sorsby fundus dystrophy (136900) in 3 successive generations, Langton et al. (2000) found a heterozygous glu139-to-ter (E139X) mutation in the TIMP3 gene. Because of a G-to-T transversion in the first base of codon 139, a normal GAG codon was replaced by a TAG termination codon.
Apte, S. S., Mattei, M.-G., Olsen, B. R. Cloning of the cDNA encoding human tissue inhibitor of metalloproteinases-3 (TIMP-3) and mapping of the TIMP3 gene to chromosome 22. Genomics 19: 86-90, 1994. [PubMed: 8188246] [Full Text: https://doi.org/10.1006/geno.1994.1016]
Ayyagari, R., Griesinger, I. B., Bingham, E., Lark, K. K., Moroi, S. E., Sieving, P. A. Autosomal dominant hemorrhagic macular dystrophy not associated with the TIMP3 gene. Arch. Ophthal. 118: 85-92, 2000. [PubMed: 10636420] [Full Text: https://doi.org/10.1001/archopht.118.1.85]
Carrero-Valenzuela, R. D., Klein, M. L., Weleber, R. G., Murphey, W. H., Litt, M. Sorsby fundus dystrophy: a family with the ser181cys mutation of the tissue inhibitor of metalloproteinases 3. Arch. Ophthal. 114: 737-738, 1996. [PubMed: 8639088] [Full Text: https://doi.org/10.1001/archopht.1996.01100130729016]
Felbor, U., Stohr, H., Amann, T., Schonherr, U., Weber, B. H. F. A novel ser156cys mutation in the tissue inhibitor of metalloproteinase-3 (TIMP3) in Sorsby's fundus dystrophy with unusual clinical features. Hum. Molec. Genet. 4: 2415-2416, 1995. [PubMed: 8634721] [Full Text: https://doi.org/10.1093/hmg/4.12.2415]
Felbor, U., Suvanto, E. A., Forsius, H. R., Eriksson, A. W., Weber, B. H. F. Autosomal recessive Sorsby fundus dystrophy revisited: molecular evidence for dominant inheritance. Am. J. Hum. Genet. 60: 57-62, 1997. [PubMed: 8981947]
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Karlin, S., Chen, C., Gentles, A. J., Cleary, M. Associations between human disease genes and overlapping gene groups and multiple amino acid runs. Proc. Nat. Acad. Sci. 99: 17008-17013, 2002. [PubMed: 12473749] [Full Text: https://doi.org/10.1073/pnas.262658799]
Langton, K. P., Barker, M. D., McKie, N. Localization of the functional domains of human tissue inhibitor of metalloproteinases-3 and the effects of a Sorsby's fundus dystrophy mutation. J. Biol. Chem. 273: 16778-16781, 1998. [PubMed: 9642234] [Full Text: https://doi.org/10.1074/jbc.273.27.16778]
Langton, K. P., McKie, N., Curtis, A., Goodship, J. A., Bond, P. M., Barker, M. D., Clarke, M. A novel tissue inhibitor of metalloproteinases-3 mutation reveals a common molecular phenotype in Sorsby's fundus dystrophy. J. Biol. Chem. 275: 27027-27031, 2000. [PubMed: 10854443] [Full Text: https://doi.org/10.1074/jbc.M909677199]
Langton, K. P., McKie, N., Smith, B. M., Brown, N. J., Barker, M. D. Sorsby's fundus dystrophy mutations impair turnover of TIMP-3 by retinal pigment epithelial cells. Hum. Molec. Genet. 14: 3579-3586, 2005. [PubMed: 16223891] [Full Text: https://doi.org/10.1093/hmg/ddi385]
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]
Mohammed, F. F., Smookler, D. S., Taylor, S. E. M., Fingleton, B., Kassiri, Z., Sanchez, O. H., English, J. L., Matrisian, L. M., Au, B., Yeh, W.-C., Khokha, R. Abnormal TNF activity in Timp3-/- mice leads to chronic hepatic inflammation and failure of liver regeneration. Nature Genet. 36: 969-977, 2004. [PubMed: 15322543] [Full Text: https://doi.org/10.1038/ng1413]
Osman, M., Tortorella, M., Londei, M., Quaratino, S. Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases define the migratory characteristics of human monocyte-derived dendritic cells. Immunology 105: 73-82, 2002. [PubMed: 11849317] [Full Text: https://doi.org/10.1046/j.0019-2805.2001.01349.x]
Qi, J. H., Ebrahem, Q., Moore, N., Murphy, G., Claesson-Welsh, L., Bond, M., Baker, A., Anand-Apte, B. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nature Med. 9: 407-415, 2003. [PubMed: 12652295] [Full Text: https://doi.org/10.1038/nm846]
Stohr, H., Roomp, K., Felbor, U., Weber, B. H. F. Genomic organization of the human tissue inhibitor of metalloproteinases-3 (TIMP3). Genome Res. 5: 483-487, 1995. [PubMed: 8808469] [Full Text: https://doi.org/10.1101/gr.5.5.483]
Weber, B. H. F., Vogt, G., Pruett, R. C., Stohr, H., Felbor, U. Mutations in the tissue inhibitor metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy. Nature Genet. 8: 352-356, 1994. [PubMed: 7894485] [Full Text: https://doi.org/10.1038/ng1294-352]
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Wild, A., Ramaswamy, A., Langer, P., Celik, I., Fendrich, V., Chaloupka, B., Simon, B., Bartsch, D. K. Frequent methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene in pancreatic endocrine tumors. J. Clin. Endocr. Metab. 88: 1367-1373, 2003. [PubMed: 12629131] [Full Text: https://doi.org/10.1210/jc.2002-021027]
Wilde, C. G., Hawkins, P. R., Coleman, R. T., Levine, W. B., Delegeane, A. M., Okamoto, P. M., Ito, L. Y., Scott, R. W., Seilhamer, J. J. Cloning and characterization of human tissue inhibitor of metalloproteinases-3. DNA Cell Biol. 13: 711-718, 1994. [PubMed: 7772252] [Full Text: https://doi.org/10.1089/dna.1994.13.711]