RBCC

Full text data of VCL

VCL [Confidence: low (only semi-automatic identification from reviews)]
Vinculin (Metavinculin; MV)

UniProt P18206
ID VINC_HUMAN Reviewed; 1134 AA.
AC P18206; Q16450; Q5SWX2; Q7Z3B8; Q8IXU7;
DT 01-NOV-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 4.
DT 22-JAN-2014, entry version 160.
DE RecName: Full=Vinculin;
DE AltName: Full=Metavinculin;
DE Short=MV;
GN Name=VCL;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Endothelial cell;
RX PubMed=2116004; DOI=10.1073/pnas.87.15.5667;
RA Weller P.A., Ogryzko E.P., Corben E.B., Zhidkova N.I., Patel B.,
RA Price G.J., Spurr N.K., Koteliansky V.E., Critchley D.R.;
RT "Complete sequence of human vinculin and assignment of the gene to
RT chromosome 10.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:5667-5671(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Retina;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP LEU-234.
RC TISSUE=Prostate;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-56, AND ALTERNATIVE SPLICING
RP (ISOFORMS 1 AND 2).
RX PubMed=8440716;
RA Moiseyeva E.P., Weller P.A., Zhidkova N.I., Corben E.B., Patel B.,
RA Jasinska I., Koteliansky V.E., Critchley D.R.;
RT "Organization of the human gene encoding the cytoskeletal protein
RT vinculin and the sequence of the vinculin promoter.";
RL J. Biol. Chem. 268:4318-4325(1993).
RN [6]
RP PROTEIN SEQUENCE OF 114-132; 247-261; 327-339; 353-366; 465-476 AND
RP 548-561, AND MASS SPECTROMETRY.
RC TISSUE=Fetal brain cortex;
RA Lubec G., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 854-1051, AND ALTERNATIVE
RP SPLICING (ISOFORM 2).
RC TISSUE=Uterus;
RX PubMed=1339348; DOI=10.1111/j.1432-1033.1992.tb16692.x;
RA Koteliansky V.E., Ogryzko E.P., Zhidkova N.I., Weller P.A.,
RA Critchley D.R., Vancompernolle K., Vandekerckhove J., Strasser P.,
RA Way M., Gimona M., Small J.V.;
RT "An additional exon in the human vinculin gene specifically encodes
RT meta-vinculin-specific difference peptide. Cross-species comparison
RT reveals variable and conserved motifs in the meta-vinculin insert.";
RL Eur. J. Biochem. 204:767-772(1992).
RN [8]
RP PROTEIN SEQUENCE OF 2-7 (ISOFORMS 1/2).
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [9]
RP PHOSPHORYLATION AT TYR-1133, AND MASS SPECTROMETRY.
RX PubMed=15229287; DOI=10.1091/mbc.E04-03-0264;
RA Zhang Z., Izaguirre G., Lin S.-Y., Lee H.Y., Schaefer E.,
RA Haimovich B.;
RT "The phosphorylation of vinculin on tyrosine residues 100 and 1065,
RT mediated by SRC kinases, affects cell spreading.";
RL Mol. Biol. Cell 15:4234-4247(2004).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-721, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [11]
RP INTERACTION WITH SYNM.
RX PubMed=18028034; DOI=10.1042/BJ20071188;
RA Sun N., Critchley D.R., Paulin D., Li Z., Robson R.M.;
RT "Human alpha-synemin interacts directly with vinculin and
RT metavinculin.";
RL Biochem. J. 409:657-667(2008).
RN [12]
RP SUBCELLULAR LOCATION.
RX PubMed=18439753; DOI=10.1016/j.canlet.2008.03.015;
RA Huggins C.J., Andrulis I.L.;
RT "Cell cycle regulated phosphorylation of LIMD1 in cell lines and
RT expression in human breast cancers.";
RL Cancer Lett. 267:55-66(2008).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-290; SER-721 AND
RP TYR-822, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [14]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-173 AND LYS-496, AND MASS
RP SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [15]
RP FUNCTION, AND DOMAIN.
RX PubMed=20484056; DOI=10.1074/jbc.M110.102830;
RA Le Clainche C., Dwivedi S.P., Didry D., Carlier M.F.;
RT "Vinculin is a dually regulated actin filament barbed end-capping and
RT side-binding protein.";
RL J. Biol. Chem. 285:23420-23432(2010).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-288; SER-290 AND
RP SER-721, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-290; SER-346; SER-434
RP AND SER-721, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [19]
RP FUNCTION (ISOFORM 2).
RX PubMed=22613835; DOI=10.1083/jcb.201111046;
RA Janssen M.E., Liu H., Volkmann N., Hanein D.;
RT "The C-terminal tail domain of metavinculin, vinculin's splice
RT variant, severs actin filaments.";
RL J. Cell Biol. 197:585-593(2012).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.42 ANGSTROMS) OF 1-258 IN COMPLEX WITH TLN1.
RX PubMed=15070891; DOI=10.1074/jbc.M403076200;
RA Izard T., Vonrhein C.;
RT "Structural basis for amplifying vinculin activation by talin.";
RL J. Biol. Chem. 279:27667-27678(2004).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.35 ANGSTROMS) OF 1-258 IN COMPLEX WITH TLN1.
RX PubMed=14702644; DOI=10.1038/nature02281;
RA Izard T., Evans G., Borgon R.A., Rush C.L., Bricogne G., Bois P.R.J.;
RT "Vinculin activation by talin through helical bundle conversion.";
RL Nature 427:171-175(2004).
RN [22]
RP VARIANTS CMD1W LEU-954 DEL AND TRP-975, AND CHARACTERIZATION OF
RP VARIANT CMD1W TRP-975.
RX PubMed=11815424; DOI=10.1161/hc0402.102930;
RA Olson T.M., Illenberger S., Kishimoto N.Y., Huttelmaier S.,
RA Keating M.T., Jockusch B.M.;
RT "Metavinculin mutations alter actin interaction in dilated
RT cardiomyopathy.";
RL Circulation 105:431-437(2002).
RN [23]
RP VARIANT CMD1W TRP-975, AND VARIANTS VAL-934 AND ALA-943.
RX PubMed=16236538; DOI=10.1016/j.ymgme.2005.08.006;
RA Vasile V.C., Will M.L., Ommen S.R., Edwards W.D., Olson T.M.,
RA Ackerman M.J.;
RT "Identification of a metavinculin missense mutation, R975W, associated
RT with both hypertrophic and dilated cardiomyopathy.";
RL Mol. Genet. Metab. 87:169-174(2006).
RN [24]
RP VARIANT CMH15 MET-277.
RX PubMed=16712796; DOI=10.1016/j.bbrc.2006.04.151;
RA Vasile V.C., Ommen S.R., Edwards W.D., Ackerman M.J.;
RT "A missense mutation in a ubiquitously expressed protein, vinculin,
RT confers susceptibility to hypertrophic cardiomyopathy.";
RL Biochem. Biophys. Res. Commun. 345:998-1003(2006).
CC -!- FUNCTION: Actin filament (F-actin)-binding protein involved in
CC cell-matrix adhesion and cell-cell adhesion. Regulates cell-
CC surface E-cadherin expression and potentiates mechanosensing by
CC the E-cadherin complex. May also play important roles in cell
CC morphology and locomotion.
CC -!- SUBUNIT: Exhibits self-association properties. Interacts with
CC APBB1IP, NRAP and SORBS1 (By similarity). Interacts with TLN1.
CC Interacts with CTNNB1 and this interaction is necessary for its
CC localization to the cell-cell junctions and for its function in
CC regulating cell surface expression of E-cadherin (By similarity).
CC Interacts with SYNM.
CC -!- INTERACTION:
CC O15144:ARPC2; NbExp=2; IntAct=EBI-716775, EBI-352356;
CC P18010:ipaA (xeno); NbExp=3; IntAct=EBI-716775, EBI-7640410;
CC Q6XVZ2:ipaA (xeno); NbExp=4; IntAct=EBI-716775, EBI-7255868;
CC Q62417-2:Sorbs1 (xeno); NbExp=3; IntAct=EBI-716775, EBI-7072893;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton. Cell junction,
CC adherens junction. Cell membrane; Peripheral membrane protein;
CC Cytoplasmic side. Cell junction, focal adhesion. Note=Cytoplasmic
CC face of adhesion plaques. Recruitment to cell-cell junctions
CC occurs in a myosin II-dependent manner. Interaction with CTNNB1 is
CC necessary for its localization to the cell-cell junctions (By
CC similarity). Colocalizes with LIMD1 in the focal adhesions.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=2; Synonyms=Metavinculin;
CC IsoId=P18206-1; Sequence=Displayed;
CC Name=1; Synonyms=Vinculin;
CC IsoId=P18206-2; Sequence=VSP_006731;
CC Name=3;
CC IsoId=P18206-3; Sequence=VSP_011857, VSP_011858, VSP_011859;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Metavinculin is muscle-specific.
CC -!- DOMAIN: Exists in at least two conformations. When in the closed,
CC 'inactive' conformation, extensive interactions between the head
CC and tail domains prevent detectable binding to most of its
CC ligands. It takes on an 'active' conformation after cooperative
CC and simultaneous binding of two different ligands. This activation
CC involves displacement of the head-tail interactions and leads to a
CC significant accumulation of ternary complexes. The active form
CC then binds a number of proteins that have both signaling and
CC structural roles that are essential for cell adhesion.
CC -!- DOMAIN: The N-terminal globular head (Vh) comprises of subdomains
CC D1-D4. The C-terminal tail (Vt) binds F-actin and cross-links
CC actin filaments into bundles. In isoform 2 (metavinculin) a 68
CC residue insertion in the tail domain promotes actin severing
CC instead of bundling. An intramolecular interaction between Vh and
CC Vt masks the F-actin-binding domain located in Vt. The binding of
CC talin and alpha-actinin to the D1 subdomain of vinculin induces a
CC helical bundle conversion of this subdomain, leading to the
CC disruption of the intramolecular interaction and the exposure of
CC the cryptic F-actin-binding domain of Vt. Vt inhibits actin
CC filament barbed end elongation without affecting the critical
CC concentration of actin assembly.
CC -!- PTM: Phosphorylated; on serines, threonines and tyrosines.
CC Phosphorylation on Tyr-1133 in activated platelets affects head-
CC tail interactions and cell spreading but has no effect on actin
CC binding nor on localization to focal adhesion plaques (By
CC similarity).
CC -!- PTM: Acetylated; mainly by myristic acid but also by a small
CC amount of palmitic acid (By similarity).
CC -!- DISEASE: Cardiomyopathy, dilated 1W (CMD1W) [MIM:611407]: A
CC disorder characterized by ventricular dilation and impaired
CC systolic function, resulting in congestive heart failure and
CC arrhythmia. Patients are at risk of premature death. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Cardiomyopathy, familial hypertrophic 15 (CMH15)
CC [MIM:613255]: A hereditary heart disorder characterized by
CC ventricular hypertrophy, which is usually asymmetric and often
CC involves the interventricular septum. The symptoms include
CC dyspnea, syncope, collapse, palpitations, and chest pain. They can
CC be readily provoked by exercise. The disorder has inter- and
CC intrafamilial variability ranging from benign to malignant forms
CC with high risk of cardiac failure and sudden cardiac death.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the vinculin/alpha-catenin family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/VCL";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Vinculin entry;
CC URL="http://en.wikipedia.org/wiki/Vinculin";
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DR EMBL; M33308; AAA61283.1; -; mRNA.
DR EMBL; BX537994; CAD97952.1; -; mRNA.
DR EMBL; AL596247; CAI13972.1; -; Genomic_DNA.
DR EMBL; AL731576; CAI13972.1; JOINED; Genomic_DNA.
DR EMBL; AL731576; CAI39673.1; -; Genomic_DNA.
DR EMBL; AL596247; CAI39673.1; JOINED; Genomic_DNA.
DR EMBL; BC039174; AAH39174.1; -; mRNA.
DR EMBL; L04933; AAA61271.1; -; Genomic_DNA.
DR EMBL; S87180; AAB21656.1; -; Genomic_DNA.
DR EMBL; S87175; AAB21656.1; JOINED; Genomic_DNA.
DR EMBL; S87178; AAB21656.1; JOINED; Genomic_DNA.
DR EMBL; S87223; AAB21657.1; -; Genomic_DNA.
DR EMBL; S87218; AAB21657.1; JOINED; Genomic_DNA.
DR PIR; A35955; A35955.
DR RefSeq; NP_003364.1; NM_003373.3.
DR RefSeq; NP_054706.1; NM_014000.2.
DR UniGene; Hs.643896; -.
DR PDB; 1RKC; X-ray; 2.70 A; A=1-258.
DR PDB; 1RKE; X-ray; 2.35 A; A=1-258, B=882-1134.
DR PDB; 1SYQ; X-ray; 2.42 A; A=1-258.
DR PDB; 1TR2; X-ray; 2.90 A; A/B=1-1134.
DR PDB; 1YDI; X-ray; 1.80 A; A=1-258.
DR PDB; 2GWW; X-ray; 2.72 A; A=1-257.
DR PDB; 2HSQ; X-ray; 3.97 A; A=2-257.
DR PDB; 2IBF; X-ray; 3.20 A; A=1-258.
DR PDB; 3H2U; X-ray; 2.75 A; A/C=879-1134.
DR PDB; 3H2V; X-ray; 2.90 A; A/B/C/D=879-1134.
DR PDB; 3MYI; X-ray; 2.20 A; A=959-1130.
DR PDB; 3RF3; X-ray; 1.61 A; A/B=1-258.
DR PDB; 3S90; X-ray; 1.97 A; A/B=1-252.
DR PDB; 3TJ5; X-ray; 1.99 A; A=1-255.
DR PDB; 3TJ6; X-ray; 2.76 A; A=1-257.
DR PDB; 3VF0; X-ray; 2.54 A; A=856-1134.
DR PDB; 4DJ9; X-ray; 2.25 A; A=1-258.
DR PDB; 4EHP; X-ray; 2.66 A; A=1-252.
DR PDBsum; 1RKC; -.
DR PDBsum; 1RKE; -.
DR PDBsum; 1SYQ; -.
DR PDBsum; 1TR2; -.
DR PDBsum; 1YDI; -.
DR PDBsum; 2GWW; -.
DR PDBsum; 2HSQ; -.
DR PDBsum; 2IBF; -.
DR PDBsum; 3H2U; -.
DR PDBsum; 3H2V; -.
DR PDBsum; 3MYI; -.
DR PDBsum; 3RF3; -.
DR PDBsum; 3S90; -.
DR PDBsum; 3TJ5; -.
DR PDBsum; 3TJ6; -.
DR PDBsum; 3VF0; -.
DR PDBsum; 4DJ9; -.
DR PDBsum; 4EHP; -.
DR ProteinModelPortal; P18206; -.
DR SMR; P18206; 1-258, 957-1134.
DR DIP; DIP-35570N; -.
DR IntAct; P18206; 19.
DR MINT; MINT-92846; -.
DR STRING; 9606.ENSP00000211998; -.
DR PhosphoSite; P18206; -.
DR DMDM; 21903479; -.
DR DOSAC-COBS-2DPAGE; P18206; -.
DR OGP; P18206; -.
DR REPRODUCTION-2DPAGE; IPI00291175; -.
DR SWISS-2DPAGE; P18206; -.
DR UCD-2DPAGE; P18206; -.
DR PaxDb; P18206; -.
DR PRIDE; P18206; -.
DR DNASU; 7414; -.
DR Ensembl; ENST00000211998; ENSP00000211998; ENSG00000035403.
DR Ensembl; ENST00000372755; ENSP00000361841; ENSG00000035403.
DR GeneID; 7414; -.
DR KEGG; hsa:7414; -.
DR UCSC; uc001jwd.3; human.
DR CTD; 7414; -.
DR GeneCards; GC10P075757; -.
DR H-InvDB; HIX0170429; -.
DR HGNC; HGNC:12665; VCL.
DR HPA; CAB002453; -.
DR HPA; HPA002131; -.
DR MIM; 193065; gene.
DR MIM; 611407; phenotype.
DR MIM; 613255; phenotype.
DR neXtProt; NX_P18206; -.
DR Orphanet; 154; Familial isolated dilated cardiomyopathy.
DR Orphanet; 155; Familial isolated hypertrophic cardiomyopathy.
DR PharmGKB; PA37288; -.
DR eggNOG; NOG329927; -.
DR HOGENOM; HOG000007828; -.
DR HOVERGEN; HBG079758; -.
DR InParanoid; P18206; -.
DR KO; K05700; -.
DR OMA; PILICSM; -.
DR OrthoDB; EOG73NG2V; -.
DR PhylomeDB; P18206; -.
DR Reactome; REACT_17044; Muscle contraction.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; VCL; human.
DR EvolutionaryTrace; P18206; -.
DR GeneWiki; Vinculin; -.
DR GenomeRNAi; 7414; -.
DR NextBio; 29028; -.
DR PRO; PR:P18206; -.
DR ArrayExpress; P18206; -.
DR Bgee; P18206; -.
DR CleanEx; HS_VCL; -.
DR Genevestigator; P18206; -.
DR GO; GO:0015629; C:actin cytoskeleton; IEA:InterPro.
DR GO; GO:0005913; C:cell-cell adherens junction; IDA:BHF-UCL.
DR GO; GO:0043034; C:costamere; ISS:UniProtKB.
DR GO; GO:0005856; C:cytoskeleton; TAS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005916; C:fascia adherens; IEA:Ensembl.
DR GO; GO:0005925; C:focal adhesion; ISS:UniProtKB.
DR GO; GO:0043234; C:protein complex; IDA:UniProtKB.
DR GO; GO:0042383; C:sarcolemma; IEA:Ensembl.
DR GO; GO:0030018; C:Z disc; IEA:Ensembl.
DR GO; GO:0003779; F:actin binding; IDA:BHF-UCL.
DR GO; GO:0008013; F:beta-catenin binding; ISS:BHF-UCL.
DR GO; GO:0045296; F:cadherin binding; ISS:BHF-UCL.
DR GO; GO:0005198; F:structural molecule activity; IEA:InterPro.
DR GO; GO:0034333; P:adherens junction assembly; IMP:BHF-UCL.
DR GO; GO:0043297; P:apical junction assembly; IMP:UniProtKB.
DR GO; GO:0007160; P:cell-matrix adhesion; TAS:BHF-UCL.
DR GO; GO:0006928; P:cellular component movement; TAS:UniProtKB.
DR GO; GO:0090136; P:epithelial cell-cell adhesion; IMP:BHF-UCL.
DR GO; GO:0030032; P:lamellipodium assembly; ISS:UniProtKB.
DR GO; GO:0002009; P:morphogenesis of an epithelium; IMP:BHF-UCL.
DR GO; GO:0006936; P:muscle contraction; TAS:Reactome.
DR GO; GO:0030336; P:negative regulation of cell migration; TAS:UniProtKB.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0034394; P:protein localization to cell surface; IMP:BHF-UCL.
DR InterPro; IPR017997; Vinculin.
DR InterPro; IPR006077; Vinculin/catenin.
DR InterPro; IPR000633; Vinculin_CS.
DR PANTHER; PTHR18914; PTHR18914; 1.
DR Pfam; PF01044; Vinculin; 3.
DR PRINTS; PR00806; VINCULIN.
DR SUPFAM; SSF47220; SSF47220; 6.
DR PROSITE; PS00663; VINCULIN_1; 1.
DR PROSITE; PS00664; VINCULIN_2; 3.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Actin-binding; Alternative splicing;
KW Cardiomyopathy; Cell adhesion; Cell junction; Cell membrane;
KW Complete proteome; Cytoplasm; Cytoskeleton; Direct protein sequencing;
KW Disease mutation; Lipoprotein; Membrane; Palmitate; Phosphoprotein;
KW Polymorphism; Reference proteome; Repeat.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 1134 Vinculin.
FT /FTId=PRO_0000064252.
FT REPEAT 259 369 1.
FT REPEAT 370 479 2.
FT REPEAT 480 589 3.
FT REGION 2 835 N-terminal globular head.
FT REGION 168 208 Talin-interaction (By similarity).
FT REGION 259 589 3 X 112 AA tandem repeats.
FT REGION 836 878 Linker (Pro-rich).
FT REGION 879 1134 C-terminal tail.
FT REGION 1003 1046 Facilitates phospholipid membrane
FT insertion (By similarity).
FT REGION 1120 1134 Facilitates phospholipid membrane
FT insertion (By similarity).
FT COMPBIAS 837 878 Pro-rich.
FT MOD_RES 173 173 N6-acetyllysine.
FT MOD_RES 288 288 Phosphoserine.
FT MOD_RES 290 290 Phosphoserine.
FT MOD_RES 346 346 Phosphoserine.
FT MOD_RES 434 434 Phosphoserine.
FT MOD_RES 496 496 N6-acetyllysine.
FT MOD_RES 537 537 Phosphotyrosine (Potential).
FT MOD_RES 721 721 Phosphoserine.
FT MOD_RES 822 822 Phosphotyrosine.
FT MOD_RES 1133 1133 Phosphotyrosine; by SRC-type Tyr-kinases.
FT VAR_SEQ 1 73 Missing (in isoform 3).
FT /FTId=VSP_011857.
FT VAR_SEQ 262 295 DTEAMKRALASIDSKLNQAKGWLRDPSASPGDAG -> VRV
FT LSGEISKIPNSPWLGVLIGTCLILYLVIFVA (in
FT isoform 3).
FT /FTId=VSP_011858.
FT VAR_SEQ 296 1134 Missing (in isoform 3).
FT /FTId=VSP_011859.
FT VAR_SEQ 916 983 Missing (in isoform 1).
FT /FTId=VSP_006731.
FT VARIANT 234 234 V -> L (in dbSNP:rs17853882).
FT /FTId=VAR_037667.
FT VARIANT 277 277 L -> M (in CMH15).
FT /FTId=VAR_035101.
FT VARIANT 934 934 A -> V (in dbSNP:rs16931179).
FT /FTId=VAR_035102.
FT VARIANT 943 943 P -> A.
FT /FTId=VAR_035103.
FT VARIANT 954 954 Missing (in CMD1W).
FT /FTId=VAR_035104.
FT VARIANT 975 975 R -> W (in CMD1W; significantly alters
FT metavinculin-mediated cross-linking of
FT actin filaments).
FT /FTId=VAR_035105.
FT STRAND 4 6
FT HELIX 7 13
FT HELIX 16 26
FT STRAND 28 30
FT STRAND 33 35
FT HELIX 38 40
FT HELIX 41 64
FT HELIX 68 97
FT HELIX 102 145
FT HELIX 146 150
FT HELIX 154 179
FT HELIX 185 218
FT STRAND 220 222
FT HELIX 223 248
FT HELIX 253 255
FT HELIX 258 274
FT HELIX 277 284
FT HELIX 294 310
FT HELIX 315 338
FT TURN 339 342
FT HELIX 343 345
FT HELIX 347 351
FT HELIX 353 393
FT TURN 394 396
FT HELIX 402 420
FT HELIX 425 447
FT TURN 448 450
FT TURN 455 458
FT HELIX 460 482
FT HELIX 493 505
FT HELIX 514 530
FT HELIX 535 561
FT HELIX 568 577
FT HELIX 579 598
FT HELIX 604 614
FT TURN 620 624
FT HELIX 625 650
FT HELIX 655 681
FT HELIX 690 714
FT HELIX 719 743
FT HELIX 746 772
FT HELIX 777 792
FT HELIX 794 806
FT TURN 811 813
FT HELIX 814 833
FT HELIX 896 909
FT HELIX 964 977
FT HELIX 986 1005
FT HELIX 1012 1037
FT HELIX 1043 1053
FT HELIX 1056 1072
FT TURN 1073 1076
FT STRAND 1077 1079
FT HELIX 1081 1113
FT STRAND 1114 1117
FT STRAND 1119 1121
FT STRAND 1128 1130
SQ SEQUENCE 1134 AA; 123799 MW; BFBD687DA836B0FA CRC64;
MPVFHTRTIE SILEPVAQQI SHLVIMHEEG EVDGKAIPDL TAPVAAVQAA VSNLVRVGKE
TVQTTEDQIL KRDMPPAFIK VENACTKLVQ AAQMLQSDPY SVPARDYLID GSRGILSGTS
DLLLTFDEAE VRKIIRVCKG ILEYLTVAEV VETMEDLVTY TKNLGPGMTK MAKMIDERQQ
ELTHQEHRVM LVNSMNTVKE LLPVLISAMK IFVTTKNSKN QGIEEALKNR NFTVEKMSAE
INEIIRVLQL TSWDEDAWAS KDTEAMKRAL ASIDSKLNQA KGWLRDPSAS PGDAGEQAIR
QILDEAGKVG ELCAGKERRE ILGTCKMLGQ MTDQVADLRA RGQGSSPVAM QKAQQVSQGL
DVLTAKVENA ARKLEAMTNS KQSIAKKIDA AQNWLADPNG GPEGEEQIRG ALAEARKIAE
LCDDPKERDD ILRSLGEISA LTSKLADLRR QGKGDSPEAR ALAKQVATAL QNLQTKTNRA
VANSRPAKAA VHLEGKIEQA QRWIDNPTVD DRGVGQAAIR GLVAEGHRLA NVMMGPYRQD
LLAKCDRVDQ LTAQLADLAA RGEGESPQAR ALASQLQDSL KDLKARMQEA MTQEVSDVFS
DTTTPIKLLA VAATAPPDAP NREEVFDERA ANFENHSGKL GATAEKAAAV GTANKSTVEG
IQASVKTARE LTPQVVSAAR ILLRNPGNQA AYEHFETMKN QWIDNVEKMT GLVDEAIDTK
SLLDASEEAI KKDLDKCKVA MANIQPQMLV AGATSIARRA NRILLVAKRE VENSEDPKFR
EAVKAASDEL SKTISPMVMD AKAVAGNISD PGLQKSFLDS GYRILGAVAK VREAFQPQEP
DFPPPPPDLE QLRLTDELAP PKPPLPEGEV PPPRPPPPEE KDEEFPEQKA GEVINQPMMM
AARQLHDEAR KWSSKPGIPA AEVGIGVVAE ADAADAAGFP VPPDMEDDYE PELLLMPSNQ
PVNQPILAAA QSLHREATKW SSKGNDIIAA AKRMALLMAE MSRLVRGGSG TKRALIQCAK
DIAKASDEVT RLAKEVAKQC TDKRIRTNLL QVCERIPTIS TQLKILSTVK ATMLGRTNIS
DEESEQATEM LVHNAQNLMQ SVKETVREAE AASIKIRTDA GFTLRWVRKT PWYQ
//

MIM 193065
*RECORD*
*FIELD* NO
193065
*FIELD* TI
*193065 VINCULIN; VCL
METAVINCULIN, INCLUDED
*FIELD* TX

DESCRIPTION

Vinculin is a cytoskeletal protein associated with the cytoplasmic face
read moreof 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).

CLONING

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.

GENE STRUCTURE

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.

MAPPING

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.

BIOCHEMICAL FEATURES

- 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.

GENE FUNCTION

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.

MOLECULAR GENETICS

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.

ANIMAL MODEL

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.

*FIELD* AV
.0001
CARDIOMYOPATHY, DILATED, 1W
VCL, 3-BP DEL, 2862GTT

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.

.0002
CARDIOMYOPATHY, DILATED, 1W
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 15
VCL, ARG975TRP

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).

.0003
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 15
VCL, LEU277MET

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.

*FIELD* RF
1. Bakolitsa, C.; Cohen, D. M.; Bankston, L. A.; Bobkov, A. A.; Cadwell,
G. W.; Jennings, L.; Critchley, D. R.; Craig, S. W.; Liddington, R.
C.: Structural basis for vinculin activation at sites of cell adhesion. Nature 430:
583-586, 2004.

2. 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.

3. 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.

4. 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.

5. 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.

6. Koteliansky, V. E.; Ogryzko, E. P.; Zhidkova, N. I.; Weller, P.
A.; Critchley, D. R.; Vancompernolle, K.; Vandekerckhove, J.; Strasser,
P.; Way, M.; Gimona, M.; Small, J. V.: An additional exon in the
human vinculin gene specifically encodes meta-vinculin-specific difference
peptide: cross-species comparison reveals variable and conserved motifs
in the meta-vinculin insert. Europ. J. Biochem. 204: 767-772, 1992.
Note: Erratum: Europ. J. Biochem. 205: 1218 only, 1992.

7. Moiseyeva, E. P.; Weller, P. A.; Zhidkova, N. I.; Corben, E. B.;
Patel, B.; Jasinka, I.; Koteliansky, V. E.; Critchley, D. R.: Organization
of the human gene encoding the cytoskeletal protein vinculin and the
sequence of the vinculin promoter. J. Biol. Chem. 268: 4318-4325,
1993.

8. Mulligan, L. M.; Gardner, E.; Telenius, H.; Ponder, B. A. J.:
Complementary physical and genetic techniques map the vinculin (VCL)
gene on chromosome 10q. Genomics 13: 1347-1349, 1992.

9. Olson, T. M.; Illenberger, S.; Kishimoto, N. Y.; Huttelmaier, S.;
Keating, M. T.; Jockusch, B. M.: Metavinculin mutations alter actin
interaction in dilated cardiomyopathy. Circulation 105: 431-437,
2002.

10. Richards, M.; Nikolski, V. P.; Green, K. G.; Zemljic-Harpf, A.
E.; Efimov, I. E.; Ross, R. S.; Saffitz, J. E.: Ventricular arrhythmias
in a mouse model of vinculin-related cardiomyopathy. Heart Rhythm 2:
S178 only, 2005.

11. Strasser, P.; Gimona, M.; Herzog, M.; Geiger, B.; Small, J. V.
: Variable and constant regions in the C-terminus of vinculin and
metavinculin: cloning and expression of fragments in E. coli. FEBS
Lett. 317: 189-194, 1993.

12. Turner, C. E.; Burridge, K.: Detection of metavinculin in human
platelets using a modified talin overlay assay. Europ. J. Cell Biol. 49:
202-206, 1989.

13. Vasile, V. C.; Edwards, W. D.; Ommen, S. R.; Ackerman, M. J.:
Obstructive hypertrophic cardiomyopathy is associated with reduced
expression of vinculin in the intercalated disc. Biochem. Biophys.
Res. Commun. 349: 709-715, 2006.

14. Vasile, V. C.; Ommen, S. R.; Edwards, W. D.; Ackerman, M. J.:
A missense mutation in a ubiquitously expressed protein, vinculin,
confers susceptibility to hypertrophic cardiomyopathy. Biochem. Biophys.
Res. Commun. 345: 998-1003, 2006.

15. Vasile, V. C.; Will, M. L.; Ommen, S. R.; Edwards, W. D.; Olson,
T. M.; Ackerman, M. J.: Identification of a metavinculin missense
mutation, R975W, associated with both hypertrophic and dilated cardiomyopathy. Molec.
Genet. Metab. 87: 169-174, 2006.

16. Weller, P. A.; Ogryzko, E. P.; Corben, E. B.; Zhidkova, N. I.;
Patel, B.; Price, G. J.; Spurr, N. K.; Koteliansky, V. E.; Critchley,
D. R.: Complete sequence of human vinculin and assignment of the
gene to chromosome 10. Proc. Nat. Acad. Sci. 87: 5667-5671, 1990.

17. Xu, W.; Baribault, H.; Adamson, E. D.: Vinculin knockout results
in heart and brain defects during embryonic development. Development 125:
327-337, 1998.

*FIELD* CN
Ada Hamosh - updated: 2/2/2011
Marla J. F. O'Neill - updated: 2/17/2010
Ada Hamosh - updated: 3/10/2009
Marla J. F. O'Neill - updated: 8/31/2007
Ada Hamosh - updated: 2/20/2007
Ada Hamosh - updated: 9/13/2004
Victor A. McKusick - updated: 4/9/2001
Victor A. McKusick - updated: 12/13/1999

*FIELD* CD
Victor A. McKusick: 8/23/1990

*FIELD* ED
carol: 04/17/2013
terry: 11/13/2012
carol: 2/15/2012
alopez: 2/3/2012
alopez: 2/7/2011
terry: 2/2/2011
wwang: 2/17/2010
alopez: 3/12/2009
terry: 3/10/2009
carol: 9/4/2007
terry: 8/31/2007
alopez: 2/21/2007
terry: 2/20/2007
alopez: 9/16/2004
terry: 9/13/2004
mcapotos: 4/11/2001
terry: 4/9/2001
mcapotos: 12/17/1999
mcapotos: 12/14/1999
terry: 12/13/1999
carol: 5/13/1993
carol: 8/17/1992
supermim: 3/16/1992
carol: 8/23/1990

MIM 611407
*RECORD*
*FIELD* NO
611407
*FIELD* TI
#611407 CARDIOMYOPATHY, DILATED, 1W; CMD1W
*FIELD* TX
A number sign (#) is used with this entry because this form of dilated
read morecardiomyopathy is caused by mutation in the gene encoding metavinculin
(VCL; 193065).

For a general phenotypic description and a discussion of genetic
heterogeneity of dilated cardiomyopathy, see CMD1A (115200).

MOLECULAR GENETICS

Olson et al. (2002) used SSCP to analyze the VCL gene, which maps to
chromosome 10q, in 350 unrelated patients with sporadic or familial
dilated cardiomyopathy 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 3
variants were located in exon 19, the metavinculin-specific exon of the
VCL gene. Low-shear viscometry studies revealed variable reductions in
viscosity associated with the variants, 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.

*FIELD* RF
1. Olson, T. M.; Illenberger, S.; Kishimoto, N. Y.; Huttelmaier, S.;
Keating, M. T.; Jockusch, B. M.: Metavinculin mutations alter actin
interaction in dilated cardiomyopathy. Circulation 105: 431-437,
2002.

*FIELD* CD
Marla J. F. O'Neill: 9/4/2007

*FIELD* ED
carol: 09/06/2007
carol: 9/4/2007

MIM 613255
*RECORD*
*FIELD* NO
613255
*FIELD* TI
#613255 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 15; CMH15
*FIELD* TX
A number sign (#) is used with this entry because familial hypertrophic
read morecardiomyopathy-15 is caused by mutation in the vinculin gene (VCL;
193065).

For a general phenotypic description and a discussion of genetic
heterogeneity of familial hypertrophic cardiomyopathy (CMH), see CMH1
(192600).

CLINICAL FEATURES

Vasile et al. (2006) studied a 43-year-old woman with severe apical
variant hypertrophic cardiomyopathy, who presented with congestive heart
failure and moderate (New York Heart Association class III) symptoms of
exertional dyspnea. Echocardiogram showed a hyperdynamic left ventricle
with an ejection fraction of 85%, systolic midcavity obliteration, and
prominent hypertrophy involving the midventricle, septum, and the apex.
Concentric severe hypertrophy was localized at the apex, with the
ventricular wall measuring approximately 16 mm at the basal septum,
increasing to 22 mm at the midventricle, and increasing further at the
apex. There was no left ventricular outflow tract obstruction. She had
mild pulmonary hypertension, with a pulmonary artery systolic pressure
of 48 mm Hg. Her family history was positive for sudden cardiac death
involving an uncle. Histologic examination of an apical myectomy
specimen confirmed the typical microscopic features of CMH, including
diffuse myocyte hypertrophy, focal myocyte disarray, focal interstitial
fibrosis, and endocardial fibrosis. Ultrastructural analysis showed no
storage vesicles or ultrastructural mitochondrial abnormalities.
Immunostaining revealed normal staining of the Z-lines but markedly
reduced vinculin/metavinculin staining in the intercalated discs.

Vasile et al. (2006) described a 76-year-old Caucasian woman who
presented with congestive heart failure and mild (NYHA class II)
symptoms of progressive exertional dyspnea, whose echocardiogram
revealed basal septal hypertrophy and a sigmoidal contoured septum
having a maximal septal wall thickness of 18 to 20 mm. There was severe
left ventricular outflow tract obstruction, with a maximum instantaneous
gradient exceeding 100 mm Hg. The patient underwent extended left
ventricular septal myomectomy due to symptoms refractory to
pharmacotherapy. Histologic examination of the specimen showed the
characteristic features of CMH, including myocyte hypertrophy and
disarray and focal interstitial fibrosis; immunostaining showed normal
Z-line staining but markedly reduced vinculin/metavinculin staining in
the intercalated discs.

MOLECULAR GENETICS

In a 43-year-old woman with severe apical variant hypertrophic
cardiomyopathy, who was negative for mutation in 8 known CMH-associated
sarcomere/myofilament-encoding genes, Vasile et al. (2006) identified a
heterozygous mutation in the VCL gene (R975W; 193065.0002). The same
mutation had previously been identified in a patient with dilated
cardiomyopathy (see CMD1W; 611407).

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) analyzed all 22 exons of the VCL gene and identified a
heterozygous mutation in a 76-year-old Caucasian woman (L277M;
193065.0003).

*FIELD* RF
1. Vasile, V. C.; Ommen, S. R.; Edwards, W. D.; Ackerman, M. J.:
A missense mutation in a ubiquitously expressed protein, vinculin,
confers susceptibility to hypertrophic cardiomyopathy. Biochem. Biophys.
Res. Commun. 345: 998-1003, 2006.

2. Vasile, V. C.; Will, M. L.; Ommen, S. R.; Edwards, W. D.; Olson,
T. M.; Ackerman, M. J.: Identification of a metavinculin missense
mutation, R975W, associated with both hypertrophic and dilated cardiomyopathy. Molec.
Genet. Metab. 87: 169-174, 2006.

*FIELD* CD
Marla J. F. O'Neill: 2/16/2010

*FIELD* ED
wwang: 02/17/2010

RBCC Red Blood Cell Collection

Full text data of VCL