Other entities represented in this entry:
HGNC Approved Gene Symbol: VCL
Cytogenetic location: 10q22.2 Genomic coordinates (GRCh38): 10:73,998,116-74,121,363 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q22.2 | Cardiomyopathy, dilated, 1W | 611407 | 3 | |
| Cardiomyopathy, hypertrophic, 15 | 613255 | Autosomal dominant | 3 |
Vinculin is a cytoskeletal protein associated with the cytoplasmic face of both cell-cell and cell-extracellular matrix adherens-type junctions, where it is thought to function as one of several interacting proteins involved in anchoring F-actin to the membrane (Weller et al., 1990).
Weller et al. (1990) determined the complete sequence of the human vinculin gene. They found that both human and chicken embryo sequences of vinculin contain 1,066 amino acids and, furthermore, that the 2 proteins exhibit a high level of sequence identity (greater than 95%). Southern blots of human genomic DNA hybridized with short vinculin cDNA fragments indicated that there is a single vinculin gene.
Koteliansky et al. (1992) determined that metavinculin is the result of alternative splicing of the VCL gene and contains an additional exon. Across species, the deduced protein differs from vinculin in having an additional insert of 68 to 79 amino acids in the C-terminal half of the molecule. By comparison of metavinculin sequences from pig, man, chicken, and frog, Strasser et al. (1993) found a division of the insert into 2 parts: the first variable and the second highly conserved. The longest insert, 79 amino acids, was found in Xenopus laevis. Three different C-terminal constructs of vinculin and metavinculin overexpressed in E. coli could be purified by column chromatography. Using amino acid sequencing methods on the intact molecules and their proteolytic subfragments, together with a polyclonal antibody specific only for metavinculin from porcine stomach, Gimona et al. (1988) identified and sequenced the insert in the porcine metavinculin molecule. By alignment with the complete sequence of chick fibroblast vinculin, they determined the exact location of the insert. In porcine metavinculin, this insert lies between the 90-kD protease-resistant N-terminal core and the C terminus of the molecule. It contains 68 amino acids and is flanked by KWSSK sequences, one of which is present in vinculin. The identity of the mapped vinculin and metavinculin sequences outside this different peptide is consistent with 2 proteins arising via alternative splicing at the mRNA level.
Moiseyeva et al. (1993) determined that the VCL gene contains 22 exons spanning greater than 75 kb. Alternative splicing of exon 19 results in the cardiac- and smooth muscle-specific metavinculin isoform, containing an additional 68 amino acids.
By use of a panel of human-rodent somatic cell hybrids, Weller et al. (1990) mapped the VCL gene to chromosome 10q11.2-qter. By linkage studies in a 3-generation family, Mulligan et al. (1992) mapped the VCL gene to chromosome 10q22.1-q23, distal to D10S22. They confirmed the assignment by hybridization of the vinculin cDNA to flow-sorted translocation derivative chromosomes containing that portion of chromosome 10.
Crystal Structure
Bakolitsa et al. (2004) described the crystal structure of the full-length vinculin molecule (1,066 amino acids), which shows a 5-domain autoinhibited conformation in which the carboxy-terminal tail domain is held pincer-like by the vinculin head, and ligand binding is regulated both sterically and allosterically. Bakolitsa et al. (2004) showed that the conformational changes in the head, tail, and proline-rich domains are linked structurally and thermodynamically, and proposed a combinatorial pathway to activation that ensures that vinculin is activated only at sites of cell adhesion when 2 or more of its binding partners are brought into apposition.
Using magnetic tweezers, total internal reflection fluorescence, and atomic force microscopy, del Rio et al. (2009) investigated the effect of force on the interaction between talin (186745), a protein that links liganded membrane integrins to the cytoskeleton, and vinculin, a focal adhesion protein that is activated by talin binding, leading to reorganization of the cytoskeleton. Application of physiologically relevant forces caused stretching of single talin rods that exposed cryptic binding sites for vinculin. Thus in the talin-vinculin system, molecular mechanotransduction can occur by protein binding after exposure of buried binding sites in the talin-vinculin system.
Turner and Burridge (1989) reported experiments indicating that vinculin is the major talin-binding protein in platelets. However, in addition, a less abundant protein of approximately 150 kD also interacted strongly with the talin fragment. Turner and Burridge (1989) confirmed that this protein is metavinculin, a protein previously believed to be confined to cardiac and smooth muscle tissue.
Hu et al. (2007) developed correlational fluorescent speckle microscopy to measure the coupling of focal adhesion proteins to actin filaments (see 102610). Different classes of focal adhesion structural and regulatory molecules exhibited varying degrees of correlated motions with actin filaments, indicating hierarchical transmission of actin motion through focal adhesions. Interactions between vinculin, talin, and actin filaments appear to constitute a slippage interface between the cytoskeleton and integrins, generating a molecular clutch that is regulated during the morphodynamic transitions of cell migration.
Using immunohistochemistry, Vasile et al. (2006) examined the pattern of vinculin/metavinculin expression in the intercalated- and Z discs of cardiomyocytes from patients with various cardiovascular conditions associated with hypertrophy. Tissue specimens derived from patients with obstructive hypertrophic cardiomyopathy (CMH; see CMH15, 613255) and aortic stenosis (see 109730) showed a universal defect of vinculin/metavinculin expression in the intercalated disc but preserved expression in the cardiac Z disc, whereas tissue specimens from patients with dilated cardiomyopathy (CMD; see CMD1W, 611407), hypertensive heart disease (see 145500), or pulmonary hypertension (see 178600) exhibited normal expression of vinculin/metavinculin in both the Z and the intercalated disc, despite being associated with hypertrophy. Vasile et al. (2006) suggested that differential expression of vinculin/metavinculin in cardiac hypertrophy might depend on the underlying pathophysiology, with localization unaffected by hemodynamic overload but expression in the intercalated disc substantially reduced by obstructive disease.
Kanchanawong et al. (2010) used 3-dimensional super-resolution fluorescence microscopy to map nanoscale protein organization in focal adhesions. Their results revealed that integrins and actin are vertically separated by an approximately 40-nm focal adhesion core region consisting of multiple protein-specific strata: a membrane-apposed integrin signaling layer containing integrin cytoplasmic tails (see 193210), focal adhesion kinase (600758), and paxillin (602505); an intermediate force-transduction layer containing talin and vinculin; and an uppermost actin-regulatory layer containing zyxin (602002), vasodilator-stimulated phosphoprotein (601703), and alpha-actinin (102575). By localizing amino- and carboxy-terminally tagged talins, Kanchanawong et al. (2010) revealed talin's polarized orientation, indicative of a role in organizing the focal adhesion strata. Kanchanawong et al. (2010) concluded that their composite multilaminar protein architecture provided a molecular blueprint for understanding focal adhesion functions.
Olson et al. (2002) used SSCP to analyze the vinculin gene in 350 unrelated patients with sporadic or familial dilated cardiomyopathy (611407) who were negative for mutations in the ACTC (102540) and TPM1 (191010) genes, and identified heterozygosity for a 3-bp in-frame deletion (L954del; 193065.0001) and a missense mutation (R975W; 193065.0002) in 2 patients, respectively. Neither mutation was found in 500 controls. A potential risk-conferring polymorphism, A934V, was identified in heterozygosity in a 30-year-old man with dilated cardiomyopathy who died 2 years after diagnosis of progressive heart failure; this variant was also found in 1 of 500 controls, a 67-year-old woman in whom electrocardiography showed abnormal T waves but echocardiogram was nondiagnostic for dilated cardiomyopathy. All variants were located in exon 19, the metavinculin-specific exon of the vinculin gene. Low-shear viscometry studies revealed variable reductions in viscosity associated with the mutations, with greater reductions caused by the L954del and R975W mutants. Fluorescence microscopy confirmed the viscosity findings, with actin organization by the A934V variant similar to wildtype, although the network appeared coarser; more prominent bundles were observed for L954del, and R975W showed the highest bundling activity. Electron microscopy of cardiac myocytes from a patient with the R975W mutation showed irregular and fragmented intercalated discs, with intact sarcomeric thin and thick filaments.
Vasile et al. (2006) analyzed the metavinculin-specific exon 19 of the VCL gene in 389 unrelated patients with hypertrophic cardiomyopathy (CMH), who were negative for mutation in 8 known CMH-associated sarcomere/myofilament-encoding genes, and identified heterozygosity for the R975W mutation in a patient with CMH15 (613255).
In a cohort of 228 CMH patients who were negative for mutation in 12 known CMH-associated sarcomere/myofilament-encoding genes, Vasile et al. (2006) performed comprehensive analysis of the 22 exons of the VCL gene and identified a heterozygous mutation in 1 patient (L277M; 193065.0003). The authors noted that despite its ubiquitous expression, the HCM-associated VCL mutation clinically yielded a cardiac-specific phenotype.
Xu et al. (1998) used a targeting vector to inactivate vinculin in embryonic stem cells, which were then injected into mice. They found that Vcl -/- embryos failed to develop beyond the tenth day of gestation and at best were two-thirds of the normal size range. The most prominent defect was lack of midline fusion of the rostral neural tube, producing a cranial bilobular appearance and attenuation of cranial and spinal nerve development. Heart development was curtailed at E9.5, with severely reduced and akinetic myocardial and endocardial structures. Somites and limbs were retarded, and ectodermal tissues were sparse and fragile. Fibroblasts isolated from mutant embryos showed reduced adhesion to fibronectin, vitronectin, laminin, and collagen compared to wildtype. In addition, migration rates over these substrata were 2-fold higher and the level of focal adhesion kinase (FAK; 600758) was 3-fold higher. Xu et al. (1998) concluded that vinculin is necessary for normal embryonic development, probably because of its role in the regulation of cell adhesion and locomotion, although specific roles in neural and cardiac development could not be ruled out.
Richards et al. (2005) analyzed hearts from Vcl +/- and wildtype mice and found that although decreased vinculin expression enhanced inducibility of ventricular arrhythmias, connexin-43 (GJA1; 121014) content and distribution, and conduction velocities, were not significantly different between mutant and wildtype mice. Richards et al. (2005) suggested that other mechanisms, such as altered integrin (see 192968) signaling, might contribute to arrhythmogenesis.
In a 39-year-old man with dilated cardiomyopathy (CMD1W; 611407), Olson et al. (2002) identified heterozygosity for a 3-bp deletion (2862delGTT) in exon 19 of the vinculin gene, resulting in the in-frame deletion of a leucine residue (leu954del). The patient's father died of heart failure at 59 years of age, and a 70-year-old paternal uncle had heart failure, but the patient's relatives declined clinical and genetic evaluation. The mutation was not found in 500 unrelated controls.
In a 57-year-old woman with dilated cardiomyopathy (CMD1W; 611407) who had undergone cardiac transplantation, Olson et al. (2002) identified heterozygosity for a 2923C-T transition in exon 19 of the vinculin gene, resulting in an arg975-to-trp (R975W) substitution in the metavinculin isoform. The mutation was also found in heterozygosity in 3 asymptomatic relatives, 2 of whom were found to have disease on screening echocardiogram: a 70-year-old maternal aunt had dilated cardiomyopathy, and a 38-year-old daughter had mild left ventricular dilation. The patient's 55-year-old sister carried the mutation but had normal left ventricular dimensions and shortening/ejection fractions. The mutation was not found in 500 unrelated controls.
In a 43-year-old woman with severe apical variant hypertrophic cardiomyopathy (CMH15; 613255), Vasile et al. (2006) identified heterozygosity for the R975W substitution in the VCL gene, located in a highly conserved residue in the tail region of metavinculin and predicted to cause significant alterations in the secondary structure and helical organization of the protein. The mutation was not found in 1,400 reference allele. Immunohistochemical analysis of the patient's myocardium demonstrated a marked reduction of both vinculin and metavinculin in the intercalated discs. Noting that the patient was homozygous for wildtype vinculin and heterozygous for R975W metavinculin, Vasile et al. (2006) suggested that the marked reduction of proteins in the intercalated discs might be due to a dominant-negative effect. However, after analyzing immunohistochemically stained tissue specimens from patients with various cardiovascular conditions associated with hypertrophy, Vasile et al. (2006) suggested that differential expression of vinculin/metavinculin in cardiac hypertrophy might depend on the underlying pathophysiology, with localization unaffected by hemodynamic overload but expression in the intercalated disc substantially reduced by obstructive disease (see GENE FUNCTION).
In a 76-year-old Caucasian woman with severely obstructive hypertrophic cardiomyopathy (CMH15; 613255), Vasile et al. (2006) identified a heterozygous 829C-A transversion in exon 8 of the VCL gene, resulting in a leu277-to-met (L277M) substitution at a conserved residue in a key functional domain. The mutation was not detected in 400 reference alleles. Immunostaining of myomectomy tissue from the patient showed normal Z line staining but markedly reduced vinculin/metavinculin staining in the intercalated discs.
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del Rio, A., Perez-Jimenez, R., Liu, R., Roca-Cusachs, P., Fernandez, J. M., Sheetz, M. P. Stretching single talin rod molecules activates vinculin binding. Science 323: 638-641, 2009. [PubMed: 19179532] [Full Text: https://doi.org/10.1126/science.1162912]
Gimona, M., Small, J. V., Moeremans, M., Van Damme, J., Puype, M., Vandekerckhove, J. Porcine vinculin and metavinculin differ by a 68-residue insert located close to the carboxy-terminal part of the molecule. EMBO J. 7: 2329-2334, 1988. [PubMed: 3142762] [Full Text: https://doi.org/10.1002/j.1460-2075.1988.tb03076.x]
Hu, K., Ji, L., Applegate, K. T., Danuser, G., Waterman-Storer, C. M. Differential transmission of actin motion within focal adhesions. Science 315: 111-115, 2007. [PubMed: 17204653] [Full Text: https://doi.org/10.1126/science.1135085]
Kanchanawong, P., Shtengel, G., Pasapera, A. M., Ramko, E. B., Davidson, M. W., Hess, H. F., Waterman, C. M. Nanoscale architecture of integrin-based cell adhesions. Nature 468: 580-584, 2010. [PubMed: 21107430] [Full Text: https://doi.org/10.1038/nature09621]
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