HGNC Approved Gene Symbol: VIM
Cytogenetic location: 10p13 Genomic coordinates (GRCh38): 10:17,228,241-17,237,593 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10p13 | Cataract 30, pulverulent | 116300 | Autosomal dominant | 3 |
Along with the microfilaments (actins) and microtubules (tubulins), the intermediate filaments represent a third class of well-characterized cytoskeletal elements. The subunits display a tissue-specific pattern of expression. Desmin (125660) is the subunit specific for muscle, and vimentin is the subunit specific for mesenchymal tissue (Quax et al., 1985).
Using a genomic clone and several recombinant cDNA clones, Perreau et al. (1988) determined the complete nucleotide sequence of the VIM coding region. Ninety percent homology was demonstrated between the hamster and human genes at the nucleotide level. The deduced 464-amino acid human protein has only 4 amino acid changes compared with hamster Vim. VIM shares structural features, including helical domains, a stretch of heptad repeats, and linker regions, with other members of the intermediate filament family. A single 2-kb mRNA species was observed in a study of mRNA from multiple different mammalian species. The 3-prime UTR includes 2 canonic polyadenylation signals.
The VIM gene was one of many that Gieser and Swaroop (1992) recovered from a subtracted cDNA library for retinal pigment epithelium. To identify candidate genes for inherited eye diseases, they prepared expressed sequence tags (ESTs) and in each instance compared the EST with published DNA sequences. Using PCR-based EST assays, they assigned to specific human chromosomes 8 of the cDNAs for which the EST did not match.
The PAL-E antibody specifically recognizes endothelial cells lining capillaries, small veins, and high endothelial venules in lymph nodes, but not endothelial cells of arteries or lymphatic capillaries. Xu et al. (2004) identified the antigen recognized by PAL-E as a secreted form of vimentin that showed an apparent molecular mass of 120 kD, in contrast with the predicted molecular mass of 55 kD. Xu et al. (2004) determined that this form was likely a homodimer linked by a disulfide bond between the single cysteine residues in each vimentin molecule, with further modification by phosphorylation. Immunoelectron microscopy of human microvascular blood endothelial cells revealed polarized expression of PAL-E-reactive vimentin along the luminal cell membrane and concentrated at discrete sites in and adjacent to endothelial vesicles. It was also detected around trapped erythrocytes, in circulating human blood, and in the culture medium of human microvascular endothelial cells.
Zhang et al. (2003) demonstrated that SP1 (189906) activated transcription from the vimentin promoter. Through N-terminal zinc fingers, ZBP89 (ZNF148; 601897) repressed SP1-mediated activation.
Although vimentin has been presumed to be important for stabilizing the architecture of the cytoplasm, Mor-Vaknin et al. (2003) found that monocyte-derived macrophages secrete vimentin into the extracellular space in vitro. Secretion of vimentin was enhanced by the proinflammatory cytokine tumor necrosis factor-alpha (TNFA; 191160) and inhibited by the antiinflammatory cytokine IL10 (124092), suggesting that vimentin is involved in the immune response. Mor-Vaknin et al. (2003) noted that vimentin likely has specialized functions that contribute to specific dynamic cellular processes.
Xu et al. (2004) found that a phosphatase inhibitor or cell activation by phorbol ester increased vimentin secretion from monocyte-derived macrophages.
Using cultured primary human dermal fibroblasts, Kueper et al. (2007) found that intermediate filament vimentin was subject to nonenzymatic N(epsilon)-carboxymethylation of lysines, predominantly those lysines located at linker regions exposed to the cytosol. Glycation, which caused redistribution of vimentin into perinuclear aggregates, was accompanied by loss of fibroblast contractile capacity. Aggregated vimentin was detected in facial skin biopsies of 3 human donors in vivo. Kueper et al. (2007) concluded that accumulation of life-long vimentin glycation contributes to loss of skin contractile properties with age.
Wang et al. (2012) showed that beclin-1 (604378), an essential autophagy and tumor suppressor protein, is a target of the protein kinase AKT (164730). Expression of a beclin-1 mutant resistant to Akt-mediated phosphorylation increased autophagy, reduced anchorage-independent growth, and inhibited Akt-driven tumorigenesis. Akt-mediated phosphorylation of beclin-1 enhanced its interactions with 14-3-3 (see 605066) and vimentin intermediate filament proteins, and vimentin depletion increased autophagy and inhibited Akt-driven transformation. Thus, Wang et al. (2012) concluded that Akt-mediated phosphorylation of beclin-1 functions in autophagy inhibition, oncogenesis, and the formation of an autophagy-inhibitory beclin-1/14-3-3/vimentin intermediate filament complex, and suggested that their findings have broad implications for understanding the role of Akt signaling and intermediate filament proteins in autophagy and cancer.
Using crosslinking and immunoprecipitation, Pang et al. (2019) found that the head domain of soluble vimentin bound to the RING domain of RNF208 (618993),. Expression of RNF208 and vimentin was inversely correlated in breast cancer samples, and RNF208 overexpression decreased vimentin protein expression and stability and increased lys27-linked polyubiquitination of vimentin at lys97. Interaction with and polyubiquitination of vimentin relied on an intact RING domain of RNF208 and phosphorylation of ser39 in the head domain of soluble vimentin. Overexpression of vimentin with a mutation at lys97, but not wildtype vimentin, rescued the reduction in cell migration caused by RNF208 overexpression. Ectopic expression of wildtype vimentin or constitutively active vimentin (i.e., with a ser39-to-asp mutation), but not inactive vimentin (i.e, with a ser39-to-ala mutation) in human breast cancer cells induced migration, which could be blocked by RNF208 overexpression.
Perreau et al. (1988) determined that the VIM gene contains 9 exons. Exon 1 is noncoding. Exon 6 contains a 30-nucleotide sequence capable of forming a hairpin structure.
Using cDNA clones of the VIM gene prepared from hamster lens mRNA, Quax et al. (1985) demonstrated that a single-copy gene encodes vimentin in man and that in man-rodent hybrid cells the gene segregates with human chromosome 10. Ferrari et al. (1987) showed by Southern blot analysis of DNA from somatic cell hybrids and by in situ chromosome hybridization that there is only 1 copy of the VIM gene, which is located on 10p13, close to IL2R (147730). Mathew et al. (1990) assigned the vimentin gene to 10p by linkage analysis.
Marcus et al. (1988) identified a BclI RFLP in the VIM gene.
Muller et al. (2009) screened 90 patients suffering from various types of cataract for mutations in the VIM gene. They identified heterozygosity for a mutation (E151K; 193060.0001) in only 1 patient, a 45-year-old female with pulverulent (dust-like) cataract (CTRCT30; 116300). The patient's mother also had cataracts.
By next-generation sequencing of 32 cataract-associated genes in 46 probands with apparently nonsyndromic congenital cataract, Ma et al. (2016) identified a heterozygous frameshift mutation (193060.0002) in the VIM gene in 1 proband (family 25). The mutation was confirmed by Sanger sequencing. The parents were not available for study.
By next-generation sequencing of 54 cataract-associated genes in 27 Han Chinese families with congenital cataract, Zhai et al. (2017) identified a heterozygous missense mutation (Q208R; 193060.0003) in the VIM gene in a proband and his father (family 14) with congenital posterior polar cataract. The paternal grandfather also had cataracts. The mutation, which was confirmed by Sanger sequencing, was not present in the mother or in 100 control individuals.
Colucci-Guyon et al. (1994) introduced a null mutation of the vimentin gene into the germline of mice. Surprisingly, animals homozygous for this mutation developed and reproduced without an obvious deviant phenotype. Immunoblotting, immunofluorescence, and immunogold labeling analyses confirmed the absence of vimentin and of the corresponding filament network. Furthermore, no compensatory expression of another intermediate filament could be demonstrated. The results leave open the question of a possible role of vimentin in unusual situations or pathologic conditions.
During mitosis, several mitotic kinases phosphorylate 11 serines in the N-terminal head domain of mouse vimentin in a spatiotemporal manner, permitting release of the intermediate filament bridge for separation of daughter cells. Matsuyama et al. (2013) created a line of mice expressing mutant vimentin in which all of these serines were mutated to alanine. Homozygous mutant mice (sa/sa mice) were viable, but their eyes were microophthalmic and their lenses were smaller than wildtype or heterozygous mice. Sa/sa mice showed abnormalities in lens epithelial cells at the equatorial germinative zone by 2 months of age, and they developed cataracts by 11 months of age. Sa/sa lens fiber cells were irregular in size and shape, had disorganized membranes, showed chromosomal instability, binucleation, and aneuploidy, and exhibited disorganized vimentin networks. Matsuyama et al. (2013) concluded that the chromosomal instability in sa/sa mice accelerated premature aging that manifested as cataracts, the classic age-related phenotype of the lens.
In a 45-year-old female with congenital pulverulent cataract (CTRCT30; 116300), Muller et al. (2009) identified a heterozygous 596G-A transition in exon 1 of the VIM gene, resulting in a glu151-to-lys (E151K) substitution in coil 1B of the protein. The mutation was not found in 192 healthy control individuals. Glu151 is a highly conserved residue. The mutant protein formed an aberrant vimentin cytoskeleton and increased the proteasome activity in transfected cells. The mutation caused a severe kinetic defect in vimentin assembly both in vitro and in vivo.
By next-generation sequencing of 32 cataract-associated genes in 46 probands with apparently nonsyndromic congenital cataract (see CTRCT30, 116300), Ma et al. (2016) identified 1 proband (family 25) with heterozygosity for a 1-bp deletion (c.15del, NM_0033380.3) in the head domain of the VIM gene, resulting in a frameshift and a premature termination codon (Val6CysfsTer26). The mutation was confirmed by Sanger sequencing. The parents were not available for study. No functional studies were performed.
By next-generation sequencing of 54 cataract-associated genes in 27 Han Chinese families with congenital cataract, Zhai et al. (2017) identified heterozygosity for a c.623A-G transition in the VIM gene, resulting in a gln208-to-arg (Q208R) substitution, in a proband and his father (family 14) with congenital posterior polar cataract (CTRCT30; 116300). The paternal grandfather also had cataracts. The mutation, which was confirmed by Sanger sequencing, was not present in the mother, but other family members were not available for testing. The mutation was not present in 100 control individuals. No functional studies were performed.
Hamosh (2017) noted that the Q208R mutation was present in 1 of 30,782 South Asian alleles in the gnomAD database (May 9, 2017).
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Pang, K., Park, J., Ahn, S. G., Lee, J., Park, Y., Ooshima, A., Mizuno, S., Yamashita, S., Park, K.-S., Lee, S-Y., Jeong, J., Ushijima, T., Yang, K.-M., Kim, S.-J. RNF208, an estrogen-inducible E3 ligase, targets soluble Vimentin to suppress metastasis in triple-negative breast cancers. Nature Commun. 10: 5805, 2019. Note: Electronic Article. [PubMed: 31862882] [Full Text: https://doi.org/10.1038/s41467-019-13852-5]
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Xu, B., deWaal, R. M., Mor-Vaknin, N., Hibbard, C., Markovitz, D. M., Kahn, M. L. The endothelial cell-specific antibody PAL-E identifies a secreted form of vimentin in the blood vasculature. Molec. Cell. Biol. 24: 9198-9206, 2004. [PubMed: 15456890] [Full Text: https://doi.org/10.1128/MCB.24.20.9198-9206.2004]
Zhai, Y., Li, J., Yu, W., Zhu, S., Yu, Y., Wu, M., Sun, G., Gong, X., Yao, K. Targeted exome sequencing of congenital cataracts related genes: broadening the mutation spectrum and genotype-phenotype correlations in 27 Chinese Han families. Sci. Rep. 7: 1219, 2017. Note: Electronic Article. [PubMed: 28450710] [Full Text: https://doi.org/10.1038/s41598-017-01182-9]
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