Full text data of VCP
VCP
[Confidence: high (present in two of the MS resources)]
Transitional endoplasmic reticulum ATPase; TER ATPase; 3.6.4.6 (15S Mg(2+)-ATPase p97 subunit; Valosin-containing protein; VCP)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Transitional endoplasmic reticulum ATPase; TER ATPase; 3.6.4.6 (15S Mg(2+)-ATPase p97 subunit; Valosin-containing protein; VCP)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00022774
IPI00022774 valosin-containing protein valosin-containing protein membrane n/a n/a n/a n/a n/a n/a n/a n/a 6 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a expected molecular weight found in band > 188 kDa together with ubiquitin
IPI00022774 valosin-containing protein valosin-containing protein membrane n/a n/a n/a n/a n/a n/a n/a n/a 6 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a expected molecular weight found in band > 188 kDa together with ubiquitin
UniProt
P55072
ID TERA_HUMAN Reviewed; 806 AA.
AC P55072; B2R5T8; Q0V924; Q2TAI5; Q969G7; Q9UCD5;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 4.
DT 22-JAN-2014, entry version 152.
DE RecName: Full=Transitional endoplasmic reticulum ATPase;
DE Short=TER ATPase;
DE EC=3.6.4.6;
DE AltName: Full=15S Mg(2+)-ATPase p97 subunit;
DE AltName: Full=Valosin-containing protein;
DE Short=VCP;
GN Name=VCP;
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 [GENOMIC DNA].
RA Lamerdin J.E., McCready P.M., Skowronski E., Adamson A.W.,
RA Burkhart-Schultz K., Gordon L., Kyle A., Ramirez M., Stilwagen S.,
RA Phan H., Velasco N., Garnes J., Danganan L., Poundstone P.,
RA Christensen M., Georgescu A., Avila J., Liu S., Attix C., Andreise T.,
RA Trankheim M., Amico-Keller G., Coefield J., Duarte S., Lucas S.,
RA Bruce R., Thomas P., Quan G., Kronmiller B., Arellano A.,
RA Montgomery M., Ow D., Nolan M., Trong S., Kobayashi A., Olsen A.O.,
RA Carrano A.V.;
RT "Sequence analysis of a human P1 clone containing the XRCC9 DNA repair
RT gene.";
RL Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pituitary;
RX PubMed=10931946; DOI=10.1073/pnas.160270997;
RA Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X.,
RA Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H.,
RA Gu B.-W., Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M., Zhou J.,
RA Xu S.-H., Gu J., Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M.,
RA Huang G.-Y., Chen Z., Chen M.-D., Chen J.-L.;
RT "Gene expression profiling in the human hypothalamus-pituitary-adrenal
RT axis and full-length cDNA cloning.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Cerebellum;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Uterus;
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 [7]
RP PROTEIN SEQUENCE OF 2-25.
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 [8]
RP PROTEIN SEQUENCE OF 2-18; 148-155; 278-287; 296-312; 366-377; 466-487;
RP 587-599; 639-651 AND 669-677, CLEAVAGE OF INITIATOR METHIONINE,
RP ACETYLATION AT ALA-2, AND MASS SPECTROMETRY.
RC TISSUE=Platelet;
RA Bienvenut W.V., Claeys D.;
RL Submitted (NOV-2005) to UniProtKB.
RN [9]
RP PROTEIN SEQUENCE OF 27-41 AND 233-238, AND INTERACTION WITH CLATHRIN.
RC TISSUE=Glial tumor;
RX PubMed=8413590; DOI=10.1038/365459a0;
RA Pleasure I.T., Black M.M., Keen J.H.;
RT "Valosin-containing protein, VCP, is a ubiquitous clathrin-binding
RT protein.";
RL Nature 365:459-462(1993).
RN [10]
RP PROTEIN SEQUENCE OF 46-53; 66-81; 96-109; 148-155; 240-251; 323-336;
RP 454-502; 530-560; 600-614; 639-651; 678-693; 714-732 AND 754-766, AND
RP MASS SPECTROMETRY.
RC TISSUE=Fetal brain cortex;
RA Lubec G., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [11]
RP PROTEIN SEQUENCE OF 314-322, MASS SPECTROMETRY, SUBCELLULAR LOCATION,
RP METHYLATION AT LYS-315, MUTAGENESIS OF LYS-315, CHARACTERIZATION OF
RP VARIANTS IBMPFD1 HIS-155 AND GLN-191, AND CHARACTERIZATION OF VARIANT
RP ALS14 GLY-159.
RX PubMed=23349634; DOI=10.1371/journal.pgen.1003210;
RA Cloutier P., Lavallee-Adam M., Faubert D., Blanchette M., Coulombe B.;
RT "A newly uncovered group of distantly related lysine
RT methyltransferases preferentially interact with molecular chaperones
RT to regulate their activity.";
RL PLoS Genet. 9:E1003210-E1003210(2013).
RN [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 388-483.
RC TISSUE=Fetal brain;
RA Dmitrenko V.V., Garifulin O.M., Kavsan V.M.;
RT "Characterization of different mRNA types expressed in human brain.";
RL Submitted (APR-1996) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP INTERACTION WITH NGLY1.
RX PubMed=15362974; DOI=10.1042/BJ20041498;
RA McNeill H., Knebel A., Arthur J.S., Cuenda A., Cohen P.;
RT "A novel UBA and UBX domain protein that binds polyubiquitin and VCP
RT and is a substrate for SAPKs.";
RL Biochem. J. 384:391-400(2004).
RN [14]
RP FUNCTION, INTERACTION WITH RNF19A, MASS SPECTROMETRY, SUBCELLULAR
RP LOCATION, AND MUTAGENESIS OF LYS-524.
RX PubMed=15456787; DOI=10.1074/jbc.M406683200;
RA Ishigaki S., Hishikawa N., Niwa J., Iemura S., Natsume T., Hori S.,
RA Kakizuka A., Tanaka K., Sobue G.;
RT "Physical and functional interaction between dorfin and valosin-
RT containing protein that are colocalized in ubiquitylated inclusions in
RT neurodegenerative disorders.";
RL J. Biol. Chem. 279:51376-51385(2004).
RN [15]
RP INTERACTION WITH VIMP.
RX PubMed=15215856; DOI=10.1038/nature02656;
RA Ye Y., Shibata Y., Yun C., Ron D., Rapoport T.A.;
RT "A membrane protein complex mediates retro-translocation from the ER
RT lumen into the cytosol.";
RL Nature 429:841-847(2004).
RN [16]
RP ISGYLATION.
RX PubMed=16139798; DOI=10.1016/j.bbrc.2005.08.132;
RA Giannakopoulos N.V., Luo J.K., Papov V., Zou W., Lenschow D.J.,
RA Jacobs B.S., Borden E.C., Li J., Virgin H.W., Zhang D.E.;
RT "Proteomic identification of proteins conjugated to ISG15 in mouse and
RT human cells.";
RL Biochem. Biophys. Res. Commun. 336:496-506(2005).
RN [17]
RP INTERACTION WITH SYVN1 AND DERL1.
RX PubMed=16289116; DOI=10.1016/j.jmb.2005.10.020;
RA Schulze A., Standera S., Buerger E., Kikkert M., van Voorden S.,
RA Wiertz E., Koning F., Kloetzel P.-M., Seeger M.;
RT "The ubiquitin-domain protein HERP forms a complex with components of
RT the endoplasmic reticulum associated degradation pathway.";
RL J. Mol. Biol. 354:1021-1027(2005).
RN [18]
RP INTERACTION WITH AMFR, FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS
RP OF LYS-251 AND LYS-524.
RX PubMed=16168377; DOI=10.1016/j.molcel.2005.08.009;
RA Song B.L., Sever N., DeBose-Boyd R.A.;
RT "Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1
RT and couples sterol-regulated ubiquitination to degradation of HMG CoA
RT reductase.";
RL Mol. Cell 19:829-840(2005).
RN [19]
RP INTERACTION WITH DERL1; AMFR; SYVN1 AND VIMP.
RX PubMed=16186510; DOI=10.1073/pnas.0505006102;
RA Ye Y., Shibata Y., Kikkert M., van Voorden S., Wiertz E.,
RA Rapoport T.A.;
RT "Recruitment of the p97 ATPase and ubiquitin ligases to the site of
RT retrotranslocation at the endoplasmic reticulum membrane.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:14132-14138(2005).
RN [20]
RP INTERACTION WITH DERL1 AND DERL2.
RX PubMed=16186509; DOI=10.1073/pnas.0505014102;
RA Lilley B.N., Ploegh H.L.;
RT "Multiprotein complexes that link dislocation, ubiquitination, and
RT extraction of misfolded proteins from the endoplasmic reticulum
RT membrane.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:14296-14301(2005).
RN [21]
RP INTERACTION WITH CASR AND RNF19A.
RX PubMed=16513638; DOI=10.1074/jbc.M513552200;
RA Huang Y., Niwa J., Sobue G., Breitwieser G.E.;
RT "Calcium-sensing receptor ubiquitination and degradation mediated by
RT the E3 ubiquitin ligase dorfin.";
RL J. Biol. Chem. 281:11610-11617(2006).
RN [22]
RP INTERACTION WITH DERL1; DERL2 AND DERL3.
RX PubMed=16449189; DOI=10.1083/jcb.200507057;
RA Oda Y., Okada T., Yoshida H., Kaufman R.J., Nagata K., Mori K.;
RT "Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein
RT response and are required for ER-associated degradation.";
RL J. Cell Biol. 172:383-393(2006).
RN [23]
RP INTERACTION WITH UBXD2.
RX PubMed=16968747; DOI=10.1242/jcs.03163;
RA Liang J., Yin C., Doong H., Fang S., Peterhoff C., Nixon R.A.,
RA Monteiro M.J.;
RT "Characterization of erasin (UBXD2): a new ER protein that promotes
RT ER-associated protein degradation.";
RL J. Cell Sci. 119:4011-4024(2006).
RN [24]
RP INTERACTION WITH TRIM13.
RX PubMed=17314412; DOI=10.1091/mbc.E06-03-0248;
RA Lerner M., Corcoran M., Cepeda D., Nielsen M.L., Zubarev R.,
RA Ponten F., Uhlen M., Hober S., Grander D., Sangfelt O.;
RT "The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 ubiquitin
RT ligase involved in ERAD.";
RL Mol. Biol. Cell 18:1670-1682(2007).
RN [25]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [26]
RP INTERACTION WITH RNF103.
RX PubMed=18675248; DOI=10.1016/j.bbrc.2008.07.126;
RA Maruyama Y., Yamada M., Takahashi K., Yamada M.;
RT "Ubiquitin ligase Kf-1 is involved in the endoplasmic reticulum-
RT associated degradation pathway.";
RL Biochem. Biophys. Res. Commun. 374:737-741(2008).
RN [27]
RP INTERACTION WITH UBXN6.
RX PubMed=18656546; DOI=10.1016/j.biocel.2008.06.008;
RA Madsen L., Andersen K.M., Prag S., Moos T., Semple C.A., Seeger M.,
RA Hartmann-Petersen R.;
RT "Ubxd1 is a novel co-factor of the human p97 ATPase.";
RL Int. J. Biochem. Cell Biol. 40:2927-2942(2008).
RN [28]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-3; THR-436 AND SER-787,
RP AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [29]
RP INTERACTION WITH TRIM21.
RX PubMed=18022694; DOI=10.1016/j.molimm.2007.10.023;
RA Takahata M., Bohgaki M., Tsukiyama T., Kondo T., Asaka M.,
RA Hatakeyama S.;
RT "Ro52 functionally interacts with IgG1 and regulates its quality
RT control via the ERAD system.";
RL Mol. Immunol. 45:2045-2054(2008).
RN [30]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [31]
RP INTERACTION WITH YOD1.
RX PubMed=19818707; DOI=10.1016/j.molcel.2009.09.016;
RA Ernst R., Mueller B., Ploegh H.L., Schlieker C.;
RT "The otubain YOD1 is a deubiquitinating enzyme that associates with
RT p97 to facilitate protein dislocation from the ER.";
RL Mol. Cell 36:28-38(2009).
RN [32]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT SER-3 AND SER-37, AND MASS SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [33]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-770 AND SER-775, AND
RP MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [34]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [35]
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 [36]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT SER-3, 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 [37]
RP INTERACTION WITH RHBDD1, MUTAGENESIS OF LYS-251; LYS-524 AND GLU-578,
RP AND MASS SPECTROMETRY.
RX PubMed=22795130; DOI=10.1016/j.molcel.2012.06.008;
RA Fleig L., Bergbold N., Sahasrabudhe P., Geiger B., Kaltak L.,
RA Lemberg M.K.;
RT "Ubiquitin-dependent intramembrane rhomboid protease promotes ERAD of
RT membrane proteins.";
RL Mol. Cell 47:558-569(2012).
RN [38]
RP FUNCTION.
RX PubMed=22020440; DOI=10.1038/ncb2367;
RA Meerang M., Ritz D., Paliwal S., Garajova Z., Bosshard M., Mailand N.,
RA Janscak P., Hubscher U., Meyer H., Ramadan K.;
RT "The ubiquitin-selective segregase VCP/p97 orchestrates the response
RT to DNA double-strand breaks.";
RL Nat. Cell Biol. 13:1376-1382(2011).
RN [39]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH L3MBTL1.
RX PubMed=22120668; DOI=10.1038/nsmb.2188;
RA Acs K., Luijsterburg M.S., Ackermann L., Salomons F.A., Hoppe T.,
RA Dantuma N.P.;
RT "The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1
RT from DNA double-strand breaks.";
RL Nat. Struct. Mol. Biol. 18:1345-1350(2011).
RN [40]
RP INTERACTION WITH SPRTN.
RX PubMed=22902628; DOI=10.1074/jbc.M112.400135;
RA Ghosal G., Leung J.W., Nair B.C., Fong K.W., Chen J.;
RT "Proliferating cell nuclear antigen (PCNA)-binding protein C1orf124 is
RT a regulator of translesion synthesis.";
RL J. Biol. Chem. 287:34225-34233(2012).
RN [41]
RP FUNCTION IN ERAD PATHWAY.
RX PubMed=22607976; DOI=10.1016/j.molcel.2012.04.015;
RA Sato T., Sako Y., Sho M., Momohara M., Suico M.A., Shuto T.,
RA Nishitoh H., Okiyoneda T., Kokame K., Kaneko M., Taura M., Miyata M.,
RA Chosa K., Koga T., Morino-Koga S., Wada I., Kai H.;
RT "STT3B-dependent posttranslational N-glycosylation as a surveillance
RT system for secretory protein.";
RL Mol. Cell 47:99-110(2012).
RN [42]
RP METHYLATION AT LYS-315, AND MUTAGENESIS OF LYS-312; ARG-313; GLU-314;
RP LYS-315; THR-316; HIS-317 AND GLY-318.
RX PubMed=22948820; DOI=10.1038/ncomms2041;
RA Kernstock S., Davydova E., Jakobsson M., Moen A., Pettersen S.,
RA Maelandsmo G.M., Egge-Jacobsen W., Falnes P.O.;
RT "Lysine methylation of VCP by a member of a novel human protein
RT methyltransferase family.";
RL Nat. Commun. 3:1038-1038(2012).
RN [43]
RP FUNCTION, AND INTERACTION WITH SPRTN.
RX PubMed=23042607; DOI=10.1038/nsmb.2394;
RA Davis E.J., Lachaud C., Appleton P., Macartney T.J., Nathke I.,
RA Rouse J.;
RT "DVC1 (C1orf124) recruits the p97 protein segregase to sites of DNA
RT damage.";
RL Nat. Struct. Mol. Biol. 19:1093-1100(2012).
RN [44]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH SPRTN.
RX PubMed=23042605; DOI=10.1038/nsmb.2395;
RA Mosbech A., Gibbs-Seymour I., Kagias K., Thorslund T., Beli P.,
RA Povlsen L., Nielsen S.V., Smedegaard S., Sedgwick G., Lukas C.,
RA Hartmann-Petersen R., Lukas J., Choudhary C., Pocock R.,
RA Bekker-Jensen S., Mailand N.;
RT "DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes
RT ubiquitin-dependent responses to replication blocks.";
RL Nat. Struct. Mol. Biol. 19:1084-1092(2012).
RN [45]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1-481 IN COMPLEX WITH ATP
RP ANALOG, CHARACTERIZATION OF VARIANTS IBMPFD1 GLY-95 AND HIS-155,
RP MUTAGENESIS OF ARG-53 AND ARG-86, AND SUBUNIT.
RX PubMed=20512113; DOI=10.1038/emboj.2010.104;
RA Tang W.K., Li D., Li C.C., Esser L., Dai R., Guo L., Xia D.;
RT "A novel ATP-dependent conformation in p97 N-D1 fragment revealed by
RT crystal structures of disease-related mutants.";
RL EMBO J. 29:2217-2229(2010).
RN [46]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 797-806 IN COMPLEX WITH PLAA.
RX PubMed=19887378; DOI=10.1074/jbc.M109.044685;
RA Qiu L., Pashkova N., Walker J.R., Winistorfer S., Allali-Hassani A.,
RA Akutsu M., Piper R., Dhe-Paganon S.;
RT "Structure and function of the PLAA/Ufd3-p97/Cdc48 complex.";
RL J. Biol. Chem. 285:365-372(2010).
RN [47]
RP VARIANTS IBMPFD1 GLY-95; CYS-155; HIS-155; PRO-155; GLN-191 AND
RP GLU-232.
RX PubMed=15034582; DOI=10.1038/ng1332;
RA Watts G.D.J., Wymer J., Kovach M.J., Mehta S.G., Mumm S., Darvish D.,
RA Pestronk A., Whyte M.P., Kimonis V.E.;
RT "Inclusion body myopathy associated with Paget disease of bone and
RT frontotemporal dementia is caused by mutant valosin-containing
RT protein.";
RL Nat. Genet. 36:377-381(2004).
RN [48]
RP VARIANT IBMPFD1 CYS-155.
RX PubMed=15732117; DOI=10.1002/ana.20407;
RA Schroeder R., Watts G.D.J., Mehta S.G., Evert B.O., Broich P.,
RA Fliessbach K., Pauls K., Hans V.H., Kimonis V., Thal D.R.;
RT "Mutant valosin-containing protein causes a novel type of
RT frontotemporal dementia.";
RL Ann. Neurol. 57:457-461(2005).
RN [49]
RP VARIANT IBMPFD1 HIS-159.
RX PubMed=16247064; DOI=10.1212/01.wnl.0000180407.15369.92;
RA Haubenberger D., Bittner R.E., Rauch-Shorny S., Zimprich F.,
RA Mannhalter C., Wagner L., Mineva I., Vass K., Auff E., Zimprich A.;
RT "Inclusion body myopathy and Paget disease is linked to a novel
RT mutation in the VCP gene.";
RL Neurology 65:1304-1305(2005).
RN [50]
RP CHARACTERIZATION OF VARIANTS IBMPFD1 GLY-95 AND HIS-155.
RX PubMed=16321991; DOI=10.1093/hmg/ddi426;
RA Weihl C.C., Dalal S., Pestronk A., Hanson P.I.;
RT "Inclusion body myopathy-associated mutations in p97/VCP impair
RT endoplasmic reticulum-associated degradation.";
RL Hum. Mol. Genet. 15:189-199(2006).
RN [51]
RP VARIANTS ALS14 HIS-155; GLY-159; GLN-191 AND ASN-592.
RX PubMed=21145000; DOI=10.1016/j.neuron.2010.11.036;
RA Johnson J.O., Mandrioli J., Benatar M., Abramzon Y., Van Deerlin V.M.,
RA Trojanowski J.Q., Gibbs J.R., Brunetti M., Gronka S., Wuu J., Ding J.,
RA McCluskey L., Martinez-Lage M., Falcone D., Hernandez D.G.,
RA Arepalli S., Chong S., Schymick J.C., Rothstein J., Landi F.,
RA Wang Y.D., Calvo A., Mora G., Sabatelli M., Monsurro M.R.,
RA Battistini S., Salvi F., Spataro R., Sola P., Borghero G., Galassi G.,
RA Scholz S.W., Taylor J.P., Restagno G., Chio A., Traynor B.J.;
RT "Exome sequencing reveals VCP mutations as a cause of familial ALS.";
RL Neuron 68:857-864(2010).
CC -!- FUNCTION: Necessary for the fragmentation of Golgi stacks during
CC mitosis and for their reassembly after mitosis. Involved in the
CC formation of the transitional endoplasmic reticulum (tER). The
CC transfer of membranes from the endoplasmic reticulum to the Golgi
CC apparatus occurs via 50-70 nm transition vesicles which derive
CC from part-rough, part-smooth transitional elements of the
CC endoplasmic reticulum (tER). Vesicle budding from the tER is an
CC ATP-dependent process. The ternary complex containing UFD1L, VCP
CC and NPLOC4 binds ubiquitinated proteins and is necessary for the
CC export of misfolded proteins from the ER to the cytoplasm, where
CC they are degraded by the proteasome. The NPLOC4-UFD1L-VCP complex
CC regulates spindle disassembly at the end of mitosis and is
CC necessary for the formation of a closed nuclear envelope.
CC Regulates E3 ubiquitin-protein ligase activity of RNF19A (By
CC similarity). Component of the VCP/p97-AMFR/gp78 complex that
CC participates in the final step of the sterol-mediated
CC ubiquitination and endoplasmic reticulum-associated degradation
CC (ERAD) of HMGCR. Also involved in DNA damage response: recruited
CC to double-strand breaks (DSBs) sites in a RNF8- and RNF168-
CC dependent manner and promotes the recruitment of TP53BP1 at DNA
CC damage sites. Recruited to stalled replication forks by SPRTN: may
CC act by mediating extraction of DNA polymerase eta (POLH) to
CC prevent excessive translesion DNA synthesis and limit the
CC incidence of mutations induced by DNA damage.
CC -!- CATALYTIC ACTIVITY: ATP + H(2)O = ADP + phosphate.
CC -!- SUBUNIT: Homohexamer. Forms a ring-shaped particle of 12.5 nm
CC diameter, that displays 6-fold radial symmetry. Part of a ternary
CC complex containing STX5A, NSFL1C and VCP. NSFL1C forms a
CC homotrimer that binds to one end of a VCP homohexamer. The complex
CC binds to membranes enriched in phosphatidylethanolamine-containing
CC lipids and promotes Golgi membrane fusion. Binds to a heterodimer
CC of NPLOC4 and UFD1L, binding to this heterodimer inhibits Golgi-
CC membrane fusion. Interaction with VCIP135 leads to dissociation of
CC the complex via ATP hydrolysis by VCP. Part of a ternary complex
CC containing NPLOC4, UFD1L and VCP. Interacts with NSFL1C-like
CC protein p37; the complex has membrane fusion activity and is
CC required for Golgi and endoplasmic reticulum biogenesis (By
CC similarity). Interacts with VIMP/SELS and SYVN1, as well as with
CC DERL1, DERL2 and DERL3; which probably transfer misfolded proteins
CC from the ER to VCP. Interacts with SVIP. Component of a complex
CC required to couple retrotranslocation, ubiquitination and
CC deglycosylation composed of NGLY1, SAKS1, AMFR, VCP and RAD23B.
CC Directly interacts with UBXD2 and RNF19A. Interacts with CASR.
CC Interacts with UBXN6, UBE4B and YOD1. Interacts with clathrin.
CC Interacts with RNF103. Interacts with TRIM13 and TRIM21. Component
CC of a VCP/p97-AMFR/gp78 complex that participates in the final step
CC of the endoplasmic reticulum-associated degradation (ERAD) of
CC HMGCR. Interacts directly with AMFR/gp78 (via its VIM). Interacts
CC with RHBDD1 (via C-terminus domain). Interacts with SPRTN; leading
CC to recruitment to stalled replication forks.
CC -!- INTERACTION:
CC Q9UKV5:AMFR; NbExp=6; IntAct=EBI-355164, EBI-1046367;
CC Q9BZE9:ASPSCR1; NbExp=3; IntAct=EBI-355164, EBI-1993677;
CC P54252:ATXN3; NbExp=8; IntAct=EBI-355164, EBI-946046;
CC P54252-1:ATXN3; NbExp=10; IntAct=EBI-355164, EBI-946068;
CC O96017:CHEK2; NbExp=2; IntAct=EBI-355164, EBI-1180783;
CC O94868:FCHSD2; NbExp=2; IntAct=EBI-355164, EBI-1215612;
CC Q9UNZ2:NSFL1C; NbExp=4; IntAct=EBI-355164, EBI-721577;
CC P26045:PTPN3; NbExp=2; IntAct=EBI-355164, EBI-1047946;
CC B1AQ61:UBE4B; NbExp=4; IntAct=EBI-355164, EBI-7931266;
CC Q92575:UBXN4; NbExp=2; IntAct=EBI-355164, EBI-723441;
CC Q9BZV1:UBXN6; NbExp=7; IntAct=EBI-355164, EBI-1993899;
CC P63104:YWHAZ; NbExp=2; IntAct=EBI-355164, EBI-347088;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol. Endoplasmic reticulum.
CC Nucleus. Note=Present in the neuronal hyaline inclusion bodies
CC specifically found in motor neurons from amyotrophic lateral
CC sclerosis patients. Present in the Lewy bodies specifically found
CC in neurons from Parkinson disease patients. Recruited to the
CC cytoplasmic surface of the endoplasmic reticulum via interaction
CC with AMFR/gp78. Following DNA double-strand breaks, recruited to
CC the sites of damage. Recruited to stalled replication forks via
CC interaction with SPRTN.
CC -!- PTM: Phosphorylated by tyrosine kinases in response to T-cell
CC antigen receptor activation (By similarity).
CC -!- PTM: ISGylated.
CC -!- PTM: Methylation at Lys-315 catalyzed by VCPKMT is increased in
CC the presence of ASPSCR1. Lys-315 methylation may decrease ATPase
CC activity.
CC -!- DISEASE: Inclusion body myopathy with early-onset Paget disease
CC with or without frontotemporal dementia 1 (IBMPFD1) [MIM:167320]:
CC An autosomal dominant disease characterized by disabling muscle
CC weakness clinically resembling to limb girdle muscular dystrophy,
CC osteolytic bone lesions consistent with Paget disease, and
CC premature frontotemporal dementia. Clinical features show
CC incomplete penetrance. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Amyotrophic lateral sclerosis 14, with or without
CC frontotemporal dementia (ALS14) [MIM:613954]: A neurodegenerative
CC disorder affecting upper motor neurons in the brain and lower
CC motor neurons in the brain stem and spinal cord, resulting in
CC fatal paralysis. Sensory abnormalities are absent. The pathologic
CC hallmarks of the disease include pallor of the corticospinal tract
CC due to loss of motor neurons, presence of ubiquitin-positive
CC inclusions within surviving motor neurons, and deposition of
CC pathologic aggregates. The etiology of amyotrophic lateral
CC sclerosis is likely to be multifactorial, involving both genetic
CC and environmental factors. The disease is inherited in 5-10% of
CC the cases. Patients with ALS14 may develop frontotemporal
CC dementia. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the AAA ATPase family.
CC -!- CAUTION: It is unclear how it participates in the recruitment of
CC TP53BP1 at DNA damage sites. According to a first report,
CC participates in the recruitment of TP53BP1 by promoting
CC ubiquitination and removal of L3MBTL1 from DNA damage sites
CC (PubMed:22120668). According to a second report, it acts by
CC removing 'Lys-48'-linked ubiquitination from sites of DNA damage
CC (PubMed:22020440).
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/VCP";
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DR EMBL; AC004472; AAC07984.1; -; Genomic_DNA.
DR EMBL; AF100752; AAD43016.1; -; mRNA.
DR EMBL; AK312310; BAG35235.1; -; mRNA.
DR EMBL; AL353795; CAH70993.1; -; Genomic_DNA.
DR EMBL; CH471071; EAW58404.1; -; Genomic_DNA.
DR EMBL; BC110913; AAI10914.1; -; mRNA.
DR EMBL; BC121794; AAI21795.1; -; mRNA.
DR EMBL; Z70768; CAA94809.1; -; mRNA.
DR PIR; T02243; T02243.
DR RefSeq; NP_009057.1; NM_007126.3.
DR UniGene; Hs.529782; -.
DR PDB; 3EBB; X-ray; 1.90 A; E/F/G/H=797-806.
DR PDB; 3HU1; X-ray; 2.81 A; A/B/C/D/E/F=1-481.
DR PDB; 3HU2; X-ray; 2.85 A; A/B/C/D/E/F=1-481.
DR PDB; 3HU3; X-ray; 2.20 A; A/B=1-481.
DR PDB; 3QC8; X-ray; 2.20 A; A=21-196.
DR PDB; 3QQ7; X-ray; 2.65 A; A=2-187.
DR PDB; 3QQ8; X-ray; 2.00 A; A=2-187.
DR PDB; 3QWZ; X-ray; 2.00 A; A=1-208.
DR PDB; 3TIW; X-ray; 1.80 A; A/B=1-187.
DR PDB; 4KLN; X-ray; 2.62 A; A/B/C/D/E/F=1-481.
DR PDB; 4KO8; X-ray; 1.98 A; A/B=1-481.
DR PDB; 4KOD; X-ray; 2.96 A; A/B/C/D/E/F/G/H/I/J/K/L=1-481.
DR PDBsum; 3EBB; -.
DR PDBsum; 3HU1; -.
DR PDBsum; 3HU2; -.
DR PDBsum; 3HU3; -.
DR PDBsum; 3QC8; -.
DR PDBsum; 3QQ7; -.
DR PDBsum; 3QQ8; -.
DR PDBsum; 3QWZ; -.
DR PDBsum; 3TIW; -.
DR PDBsum; 4KLN; -.
DR PDBsum; 4KO8; -.
DR PDBsum; 4KOD; -.
DR ProteinModelPortal; P55072; -.
DR SMR; P55072; 10-763.
DR DIP; DIP-33543N; -.
DR IntAct; P55072; 55.
DR MINT; MINT-272884; -.
DR STRING; 9606.ENSP00000351777; -.
DR BindingDB; P55072; -.
DR ChEMBL; CHEMBL1075145; -.
DR TCDB; 3.A.16.1.1; the endoplasmic reticular retrotranslocon (er-rt) family.
DR PhosphoSite; P55072; -.
DR DMDM; 6094447; -.
DR DOSAC-COBS-2DPAGE; P55072; -.
DR OGP; P55072; -.
DR REPRODUCTION-2DPAGE; IPI00022774; -.
DR REPRODUCTION-2DPAGE; P55072; -.
DR PaxDb; P55072; -.
DR PRIDE; P55072; -.
DR Ensembl; ENST00000358901; ENSP00000351777; ENSG00000165280.
DR GeneID; 7415; -.
DR KEGG; hsa:7415; -.
DR UCSC; uc003zvy.2; human.
DR CTD; 7415; -.
DR GeneCards; GC09M035056; -.
DR HGNC; HGNC:12666; VCP.
DR HPA; CAB005593; -.
DR HPA; HPA012728; -.
DR HPA; HPA012814; -.
DR MIM; 167320; phenotype.
DR MIM; 601023; gene.
DR MIM; 613954; phenotype.
DR neXtProt; NX_P55072; -.
DR Orphanet; 329478; Adult-onset distal myopathy due to VCP mutation.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR Orphanet; 52430; Inclusion body myopathy with Paget disease of bone and frontotemporal dementia.
DR Orphanet; 329475; Spastic paraplegia - Paget disease of bone.
DR PharmGKB; PA37289; -.
DR eggNOG; COG0464; -.
DR HOGENOM; HOG000223224; -.
DR HOVERGEN; HBG001226; -.
DR InParanoid; P55072; -.
DR KO; K13525; -.
DR OMA; DKFLKYG; -.
DR OrthoDB; EOG7H4DSW; -.
DR SignaLink; P55072; -.
DR ChiTaRS; VCP; human.
DR EvolutionaryTrace; P55072; -.
DR GeneWiki; Valosin-containing_protein; -.
DR GenomeRNAi; 7415; -.
DR NextBio; 29034; -.
DR PRO; PR:P55072; -.
DR ArrayExpress; P55072; -.
DR Bgee; P55072; -.
DR CleanEx; HS_VCP; -.
DR Genevestigator; P55072; -.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005811; C:lipid particle; IDA:MGI.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0000502; C:proteasome complex; IDA:BHF-UCL.
DR GO; GO:0035861; C:site of double-strand break; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0016887; F:ATPase activity; TAS:UniProtKB.
DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW.
DR GO; GO:0031593; F:polyubiquitin binding; IDA:BHF-UCL.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; ISS:UniProtKB.
DR GO; GO:0006302; P:double-strand break repair; IDA:UniProtKB.
DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; TAS:UniProtKB.
DR GO; GO:0030433; P:ER-associated ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IDA:BHF-UCL.
DR GO; GO:0031334; P:positive regulation of protein complex assembly; IDA:BHF-UCL.
DR GO; GO:0018279; P:protein N-linked glycosylation via asparagine; IMP:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB.
DR GO; GO:0030970; P:retrograde protein transport, ER to cytosol; IDA:UniProtKB.
DR GO; GO:0019985; P:translesion synthesis; IMP:UniProtKB.
DR InterPro; IPR003593; AAA+_ATPase.
DR InterPro; IPR005938; AAA_ATPase_CDC48.
DR InterPro; IPR009010; Asp_de-COase-like_dom.
DR InterPro; IPR003959; ATPase_AAA_core.
DR InterPro; IPR003960; ATPase_AAA_CS.
DR InterPro; IPR004201; Cdc48_dom2.
DR InterPro; IPR003338; CDC4_N-term_subdom.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR015415; Vps4_C.
DR Pfam; PF00004; AAA; 2.
DR Pfam; PF02933; CDC48_2; 1.
DR Pfam; PF02359; CDC48_N; 1.
DR Pfam; PF09336; Vps4_C; 1.
DR SMART; SM00382; AAA; 2.
DR SMART; SM01072; CDC48_2; 1.
DR SMART; SM01073; CDC48_N; 1.
DR SUPFAM; SSF50692; SSF50692; 1.
DR SUPFAM; SSF52540; SSF52540; 2.
DR TIGRFAMs; TIGR01243; CDC48; 1.
DR PROSITE; PS00674; AAA; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Amyotrophic lateral sclerosis; ATP-binding;
KW Complete proteome; Cytoplasm; Direct protein sequencing;
KW Disease mutation; DNA damage; DNA repair; Endoplasmic reticulum;
KW Hydrolase; Lipid-binding; Methylation; Neurodegeneration;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Transport; Ubl conjugation; Ubl conjugation pathway.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 806 Transitional endoplasmic reticulum
FT ATPase.
FT /FTId=PRO_0000084572.
FT NP_BIND 247 253 ATP.
FT REGION 797 806 Interaction with UBXN6.
FT BINDING 348 348 ATP.
FT BINDING 384 384 ATP.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 3 3 Phosphoserine.
FT MOD_RES 37 37 Phosphoserine.
FT MOD_RES 315 315 N6,N6,N6-trimethyllysine; by VCPKMT.
FT MOD_RES 436 436 Phosphothreonine.
FT MOD_RES 770 770 Phosphoserine.
FT MOD_RES 775 775 Phosphoserine.
FT MOD_RES 787 787 Phosphoserine.
FT MOD_RES 805 805 Phosphotyrosine (By similarity).
FT VARIANT 95 95 R -> G (in IBMPFD1; cultured cells
FT expressing the mutant protein show a
FT marked general increase in the level of
FT ubiquitin-conjugated proteins and
FT impaired protein degradation through the
FT endoplasmic reticulum-associated
FT degradation (ERAD) pathway; shows
FT strongly reduced affinity for ADP and
FT increased affinity for ATP; abolishes
FT enhancement of K-315 methylation by
FT ASPSCR1).
FT /FTId=VAR_033016.
FT VARIANT 155 155 R -> C (in IBMPFD1; also in one patient
FT without evidence of Paget disease of the
FT bone).
FT /FTId=VAR_033017.
FT VARIANT 155 155 R -> H (in ALS14 and IBMPFD1; ALS14
FT patients do not manifest frontotemporal
FT dementia; properly assembles into a
FT hexameric structure and shows normal
FT ATPase activity; cultured cells
FT expressing the mutant protein show a
FT marked general increase in the level of
FT ubiquitin-conjugated proteins and
FT impaired protein degradation through the
FT endoplasmic reticulum-associated
FT degradation (ERAD) pathway; shows
FT strongly reduced affinity for ADP and
FT increased affinity for ATP).
FT /FTId=VAR_033018.
FT VARIANT 155 155 R -> P (in IBMPFD1).
FT /FTId=VAR_033019.
FT VARIANT 159 159 R -> G (in ALS14).
FT /FTId=VAR_065910.
FT VARIANT 159 159 R -> H (in IBMPFD1; without
FT frontotemporal dementia; abolishes
FT enhancement of K-315 methylation by
FT ASPSCR1).
FT /FTId=VAR_033020.
FT VARIANT 191 191 R -> Q (in ALS14 and IBMPFD1; abolishes
FT enhancement of K-315 methylation by
FT ASPSCR1).
FT /FTId=VAR_033021.
FT VARIANT 232 232 A -> E (in IBMPFD1).
FT /FTId=VAR_033022.
FT VARIANT 592 592 D -> N (in ALS14; ALS14 patients do not
FT show frontotemporal dementia).
FT /FTId=VAR_065911.
FT MUTAGEN 53 53 R->A: Minor effect on affinity for ATP
FT and ADP.
FT MUTAGEN 86 86 R->A: Strongly increased affinity for
FT ATP. Strongly reduced affinity for ADP.
FT MUTAGEN 251 251 K->Q: Impairs ERAD degradation of HMGCR
FT and does not inhibit interaction with
FT RHBDD1; when associated with Q-524.
FT MUTAGEN 312 312 K->A: Does not affect methylation by
FT VCPKMT.
FT MUTAGEN 313 313 R->A: Does not affect methylation by
FT VCPKMT.
FT MUTAGEN 314 314 E->A: Does not affect methylation by
FT VCPKMT.
FT MUTAGEN 314 314 Missing: Strongly impairs methylation by
FT VCPKMT.
FT MUTAGEN 315 315 K->L,Q,R: Abolishes methylation by
FT VCPKMT.
FT MUTAGEN 316 316 T->A: Does not affect methylation by
FT VCPKMT.
FT MUTAGEN 317 317 H->A: Does not affect methylation by
FT VCPKMT.
FT MUTAGEN 318 318 G->A: Does not affect methylation by
FT VCPKMT.
FT MUTAGEN 524 524 K->A: Impairs catalytic activity of
FT RNF19A toward SOD1 mutant. Does not
FT inhibit interaction with RHBDD1; when
FT associated with A-251.
FT MUTAGEN 524 524 K->Q: Impairs ERAD degradation of HMGCR;
FT when associated with Q-251.
FT MUTAGEN 578 578 E->Q: Does not inhibit interaction with
FT RHBDD1.
FT CONFLICT 169 169 D -> H (in Ref. 6; AAI21795).
FT CONFLICT 312 312 K -> I (in Ref. 3; BAG35235).
FT HELIX 14 17
FT STRAND 25 30
FT STRAND 38 41
FT HELIX 43 49
FT STRAND 56 60
FT HELIX 62 64
FT STRAND 66 73
FT STRAND 75 77
FT STRAND 81 84
FT HELIX 86 91
FT STRAND 99 104
FT STRAND 112 118
FT HELIX 120 122
FT HELIX 123 126
FT HELIX 130 133
FT HELIX 135 139
FT TURN 140 142
FT STRAND 145 147
FT STRAND 151 155
FT STRAND 157 175
FT STRAND 181 183
FT HELIX 193 195
FT HELIX 203 205
FT HELIX 210 219
FT HELIX 221 225
FT HELIX 227 233
FT STRAND 240 244
FT HELIX 251 261
FT STRAND 263 270
FT HELIX 271 275
FT HELIX 281 295
FT STRAND 298 305
FT HELIX 306 309
FT STRAND 313 315
FT HELIX 319 334
FT HELIX 337 339
FT STRAND 341 348
FT HELIX 350 352
FT HELIX 355 358
FT STRAND 365 368
FT HELIX 374 384
FT TURN 385 387
FT HELIX 396 401
FT HELIX 408 424
FT TURN 425 429
FT STRAND 432 436
FT HELIX 439 444
FT HELIX 449 456
FT HELIX 459 465
FT HELIX 466 468
SQ SEQUENCE 806 AA; 89322 MW; 501B721D3A77BA8A CRC64;
MASGADSKGD DLSTAILKQK NRPNRLIVDE AINEDNSVVS LSQPKMDELQ LFRGDTVLLK
GKKRREAVCI VLSDDTCSDE KIRMNRVVRN NLRVRLGDVI SIQPCPDVKY GKRIHVLPID
DTVEGITGNL FEVYLKPYFL EAYRPIRKGD IFLVRGGMRA VEFKVVETDP SPYCIVAPDT
VIHCEGEPIK REDEEESLNE VGYDDIGGCR KQLAQIKEMV ELPLRHPALF KAIGVKPPRG
ILLYGPPGTG KTLIARAVAN ETGAFFFLIN GPEIMSKLAG ESESNLRKAF EEAEKNAPAI
IFIDELDAIA PKREKTHGEV ERRIVSQLLT LMDGLKQRAH VIVMAATNRP NSIDPALRRF
GRFDREVDIG IPDATGRLEI LQIHTKNMKL ADDVDLEQVA NETHGHVGAD LAALCSEAAL
QAIRKKMDLI DLEDETIDAE VMNSLAVTMD DFRWALSQSN PSALRETVVE VPQVTWEDIG
GLEDVKRELQ ELVQYPVEHP DKFLKFGMTP SKGVLFYGPP GCGKTLLAKA IANECQANFI
SIKGPELLTM WFGESEANVR EIFDKARQAA PCVLFFDELD SIAKARGGNI GDGGGAADRV
INQILTEMDG MSTKKNVFII GATNRPDIID PAILRPGRLD QLIYIPLPDE KSRVAILKAN
LRKSPVAKDV DLEFLAKMTN GFSGADLTEI CQRACKLAIR ESIESEIRRE RERQTNPSAM
EVEEDDPVPE IRRDHFEEAM RFARRSVSDN DIRKYEMFAQ TLQQSRGFGS FRFPSGNQGG
AGPSQGSGGG TGGSVYTEDN DDDLYG
//
ID TERA_HUMAN Reviewed; 806 AA.
AC P55072; B2R5T8; Q0V924; Q2TAI5; Q969G7; Q9UCD5;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 4.
DT 22-JAN-2014, entry version 152.
DE RecName: Full=Transitional endoplasmic reticulum ATPase;
DE Short=TER ATPase;
DE EC=3.6.4.6;
DE AltName: Full=15S Mg(2+)-ATPase p97 subunit;
DE AltName: Full=Valosin-containing protein;
DE Short=VCP;
GN Name=VCP;
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 [GENOMIC DNA].
RA Lamerdin J.E., McCready P.M., Skowronski E., Adamson A.W.,
RA Burkhart-Schultz K., Gordon L., Kyle A., Ramirez M., Stilwagen S.,
RA Phan H., Velasco N., Garnes J., Danganan L., Poundstone P.,
RA Christensen M., Georgescu A., Avila J., Liu S., Attix C., Andreise T.,
RA Trankheim M., Amico-Keller G., Coefield J., Duarte S., Lucas S.,
RA Bruce R., Thomas P., Quan G., Kronmiller B., Arellano A.,
RA Montgomery M., Ow D., Nolan M., Trong S., Kobayashi A., Olsen A.O.,
RA Carrano A.V.;
RT "Sequence analysis of a human P1 clone containing the XRCC9 DNA repair
RT gene.";
RL Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pituitary;
RX PubMed=10931946; DOI=10.1073/pnas.160270997;
RA Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X.,
RA Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H.,
RA Gu B.-W., Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M., Zhou J.,
RA Xu S.-H., Gu J., Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M.,
RA Huang G.-Y., Chen Z., Chen M.-D., Chen J.-L.;
RT "Gene expression profiling in the human hypothalamus-pituitary-adrenal
RT axis and full-length cDNA cloning.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Cerebellum;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Uterus;
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 [7]
RP PROTEIN SEQUENCE OF 2-25.
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 [8]
RP PROTEIN SEQUENCE OF 2-18; 148-155; 278-287; 296-312; 366-377; 466-487;
RP 587-599; 639-651 AND 669-677, CLEAVAGE OF INITIATOR METHIONINE,
RP ACETYLATION AT ALA-2, AND MASS SPECTROMETRY.
RC TISSUE=Platelet;
RA Bienvenut W.V., Claeys D.;
RL Submitted (NOV-2005) to UniProtKB.
RN [9]
RP PROTEIN SEQUENCE OF 27-41 AND 233-238, AND INTERACTION WITH CLATHRIN.
RC TISSUE=Glial tumor;
RX PubMed=8413590; DOI=10.1038/365459a0;
RA Pleasure I.T., Black M.M., Keen J.H.;
RT "Valosin-containing protein, VCP, is a ubiquitous clathrin-binding
RT protein.";
RL Nature 365:459-462(1993).
RN [10]
RP PROTEIN SEQUENCE OF 46-53; 66-81; 96-109; 148-155; 240-251; 323-336;
RP 454-502; 530-560; 600-614; 639-651; 678-693; 714-732 AND 754-766, AND
RP MASS SPECTROMETRY.
RC TISSUE=Fetal brain cortex;
RA Lubec G., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [11]
RP PROTEIN SEQUENCE OF 314-322, MASS SPECTROMETRY, SUBCELLULAR LOCATION,
RP METHYLATION AT LYS-315, MUTAGENESIS OF LYS-315, CHARACTERIZATION OF
RP VARIANTS IBMPFD1 HIS-155 AND GLN-191, AND CHARACTERIZATION OF VARIANT
RP ALS14 GLY-159.
RX PubMed=23349634; DOI=10.1371/journal.pgen.1003210;
RA Cloutier P., Lavallee-Adam M., Faubert D., Blanchette M., Coulombe B.;
RT "A newly uncovered group of distantly related lysine
RT methyltransferases preferentially interact with molecular chaperones
RT to regulate their activity.";
RL PLoS Genet. 9:E1003210-E1003210(2013).
RN [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 388-483.
RC TISSUE=Fetal brain;
RA Dmitrenko V.V., Garifulin O.M., Kavsan V.M.;
RT "Characterization of different mRNA types expressed in human brain.";
RL Submitted (APR-1996) to the EMBL/GenBank/DDBJ databases.
RN [13]
RP INTERACTION WITH NGLY1.
RX PubMed=15362974; DOI=10.1042/BJ20041498;
RA McNeill H., Knebel A., Arthur J.S., Cuenda A., Cohen P.;
RT "A novel UBA and UBX domain protein that binds polyubiquitin and VCP
RT and is a substrate for SAPKs.";
RL Biochem. J. 384:391-400(2004).
RN [14]
RP FUNCTION, INTERACTION WITH RNF19A, MASS SPECTROMETRY, SUBCELLULAR
RP LOCATION, AND MUTAGENESIS OF LYS-524.
RX PubMed=15456787; DOI=10.1074/jbc.M406683200;
RA Ishigaki S., Hishikawa N., Niwa J., Iemura S., Natsume T., Hori S.,
RA Kakizuka A., Tanaka K., Sobue G.;
RT "Physical and functional interaction between dorfin and valosin-
RT containing protein that are colocalized in ubiquitylated inclusions in
RT neurodegenerative disorders.";
RL J. Biol. Chem. 279:51376-51385(2004).
RN [15]
RP INTERACTION WITH VIMP.
RX PubMed=15215856; DOI=10.1038/nature02656;
RA Ye Y., Shibata Y., Yun C., Ron D., Rapoport T.A.;
RT "A membrane protein complex mediates retro-translocation from the ER
RT lumen into the cytosol.";
RL Nature 429:841-847(2004).
RN [16]
RP ISGYLATION.
RX PubMed=16139798; DOI=10.1016/j.bbrc.2005.08.132;
RA Giannakopoulos N.V., Luo J.K., Papov V., Zou W., Lenschow D.J.,
RA Jacobs B.S., Borden E.C., Li J., Virgin H.W., Zhang D.E.;
RT "Proteomic identification of proteins conjugated to ISG15 in mouse and
RT human cells.";
RL Biochem. Biophys. Res. Commun. 336:496-506(2005).
RN [17]
RP INTERACTION WITH SYVN1 AND DERL1.
RX PubMed=16289116; DOI=10.1016/j.jmb.2005.10.020;
RA Schulze A., Standera S., Buerger E., Kikkert M., van Voorden S.,
RA Wiertz E., Koning F., Kloetzel P.-M., Seeger M.;
RT "The ubiquitin-domain protein HERP forms a complex with components of
RT the endoplasmic reticulum associated degradation pathway.";
RL J. Mol. Biol. 354:1021-1027(2005).
RN [18]
RP INTERACTION WITH AMFR, FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS
RP OF LYS-251 AND LYS-524.
RX PubMed=16168377; DOI=10.1016/j.molcel.2005.08.009;
RA Song B.L., Sever N., DeBose-Boyd R.A.;
RT "Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1
RT and couples sterol-regulated ubiquitination to degradation of HMG CoA
RT reductase.";
RL Mol. Cell 19:829-840(2005).
RN [19]
RP INTERACTION WITH DERL1; AMFR; SYVN1 AND VIMP.
RX PubMed=16186510; DOI=10.1073/pnas.0505006102;
RA Ye Y., Shibata Y., Kikkert M., van Voorden S., Wiertz E.,
RA Rapoport T.A.;
RT "Recruitment of the p97 ATPase and ubiquitin ligases to the site of
RT retrotranslocation at the endoplasmic reticulum membrane.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:14132-14138(2005).
RN [20]
RP INTERACTION WITH DERL1 AND DERL2.
RX PubMed=16186509; DOI=10.1073/pnas.0505014102;
RA Lilley B.N., Ploegh H.L.;
RT "Multiprotein complexes that link dislocation, ubiquitination, and
RT extraction of misfolded proteins from the endoplasmic reticulum
RT membrane.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:14296-14301(2005).
RN [21]
RP INTERACTION WITH CASR AND RNF19A.
RX PubMed=16513638; DOI=10.1074/jbc.M513552200;
RA Huang Y., Niwa J., Sobue G., Breitwieser G.E.;
RT "Calcium-sensing receptor ubiquitination and degradation mediated by
RT the E3 ubiquitin ligase dorfin.";
RL J. Biol. Chem. 281:11610-11617(2006).
RN [22]
RP INTERACTION WITH DERL1; DERL2 AND DERL3.
RX PubMed=16449189; DOI=10.1083/jcb.200507057;
RA Oda Y., Okada T., Yoshida H., Kaufman R.J., Nagata K., Mori K.;
RT "Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein
RT response and are required for ER-associated degradation.";
RL J. Cell Biol. 172:383-393(2006).
RN [23]
RP INTERACTION WITH UBXD2.
RX PubMed=16968747; DOI=10.1242/jcs.03163;
RA Liang J., Yin C., Doong H., Fang S., Peterhoff C., Nixon R.A.,
RA Monteiro M.J.;
RT "Characterization of erasin (UBXD2): a new ER protein that promotes
RT ER-associated protein degradation.";
RL J. Cell Sci. 119:4011-4024(2006).
RN [24]
RP INTERACTION WITH TRIM13.
RX PubMed=17314412; DOI=10.1091/mbc.E06-03-0248;
RA Lerner M., Corcoran M., Cepeda D., Nielsen M.L., Zubarev R.,
RA Ponten F., Uhlen M., Hober S., Grander D., Sangfelt O.;
RT "The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 ubiquitin
RT ligase involved in ERAD.";
RL Mol. Biol. Cell 18:1670-1682(2007).
RN [25]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III,
RA Hurov K.E., Luo J., Bakalarski C.E., Zhao Z., Solimini N.,
RA Lerenthal Y., Shiloh Y., Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [26]
RP INTERACTION WITH RNF103.
RX PubMed=18675248; DOI=10.1016/j.bbrc.2008.07.126;
RA Maruyama Y., Yamada M., Takahashi K., Yamada M.;
RT "Ubiquitin ligase Kf-1 is involved in the endoplasmic reticulum-
RT associated degradation pathway.";
RL Biochem. Biophys. Res. Commun. 374:737-741(2008).
RN [27]
RP INTERACTION WITH UBXN6.
RX PubMed=18656546; DOI=10.1016/j.biocel.2008.06.008;
RA Madsen L., Andersen K.M., Prag S., Moos T., Semple C.A., Seeger M.,
RA Hartmann-Petersen R.;
RT "Ubxd1 is a novel co-factor of the human p97 ATPase.";
RL Int. J. Biochem. Cell Biol. 40:2927-2942(2008).
RN [28]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-3; THR-436 AND SER-787,
RP AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [29]
RP INTERACTION WITH TRIM21.
RX PubMed=18022694; DOI=10.1016/j.molimm.2007.10.023;
RA Takahata M., Bohgaki M., Tsukiyama T., Kondo T., Asaka M.,
RA Hatakeyama S.;
RT "Ro52 functionally interacts with IgG1 and regulates its quality
RT control via the ERAD system.";
RL Mol. Immunol. 45:2045-2054(2008).
RN [30]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [31]
RP INTERACTION WITH YOD1.
RX PubMed=19818707; DOI=10.1016/j.molcel.2009.09.016;
RA Ernst R., Mueller B., Ploegh H.L., Schlieker C.;
RT "The otubain YOD1 is a deubiquitinating enzyme that associates with
RT p97 to facilitate protein dislocation from the ER.";
RL Mol. Cell 36:28-38(2009).
RN [32]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT SER-3 AND SER-37, AND MASS SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [33]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-770 AND SER-775, AND
RP MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [34]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [35]
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 [36]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, PHOSPHORYLATION [LARGE
RP SCALE ANALYSIS] AT SER-3, 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 [37]
RP INTERACTION WITH RHBDD1, MUTAGENESIS OF LYS-251; LYS-524 AND GLU-578,
RP AND MASS SPECTROMETRY.
RX PubMed=22795130; DOI=10.1016/j.molcel.2012.06.008;
RA Fleig L., Bergbold N., Sahasrabudhe P., Geiger B., Kaltak L.,
RA Lemberg M.K.;
RT "Ubiquitin-dependent intramembrane rhomboid protease promotes ERAD of
RT membrane proteins.";
RL Mol. Cell 47:558-569(2012).
RN [38]
RP FUNCTION.
RX PubMed=22020440; DOI=10.1038/ncb2367;
RA Meerang M., Ritz D., Paliwal S., Garajova Z., Bosshard M., Mailand N.,
RA Janscak P., Hubscher U., Meyer H., Ramadan K.;
RT "The ubiquitin-selective segregase VCP/p97 orchestrates the response
RT to DNA double-strand breaks.";
RL Nat. Cell Biol. 13:1376-1382(2011).
RN [39]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH L3MBTL1.
RX PubMed=22120668; DOI=10.1038/nsmb.2188;
RA Acs K., Luijsterburg M.S., Ackermann L., Salomons F.A., Hoppe T.,
RA Dantuma N.P.;
RT "The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1
RT from DNA double-strand breaks.";
RL Nat. Struct. Mol. Biol. 18:1345-1350(2011).
RN [40]
RP INTERACTION WITH SPRTN.
RX PubMed=22902628; DOI=10.1074/jbc.M112.400135;
RA Ghosal G., Leung J.W., Nair B.C., Fong K.W., Chen J.;
RT "Proliferating cell nuclear antigen (PCNA)-binding protein C1orf124 is
RT a regulator of translesion synthesis.";
RL J. Biol. Chem. 287:34225-34233(2012).
RN [41]
RP FUNCTION IN ERAD PATHWAY.
RX PubMed=22607976; DOI=10.1016/j.molcel.2012.04.015;
RA Sato T., Sako Y., Sho M., Momohara M., Suico M.A., Shuto T.,
RA Nishitoh H., Okiyoneda T., Kokame K., Kaneko M., Taura M., Miyata M.,
RA Chosa K., Koga T., Morino-Koga S., Wada I., Kai H.;
RT "STT3B-dependent posttranslational N-glycosylation as a surveillance
RT system for secretory protein.";
RL Mol. Cell 47:99-110(2012).
RN [42]
RP METHYLATION AT LYS-315, AND MUTAGENESIS OF LYS-312; ARG-313; GLU-314;
RP LYS-315; THR-316; HIS-317 AND GLY-318.
RX PubMed=22948820; DOI=10.1038/ncomms2041;
RA Kernstock S., Davydova E., Jakobsson M., Moen A., Pettersen S.,
RA Maelandsmo G.M., Egge-Jacobsen W., Falnes P.O.;
RT "Lysine methylation of VCP by a member of a novel human protein
RT methyltransferase family.";
RL Nat. Commun. 3:1038-1038(2012).
RN [43]
RP FUNCTION, AND INTERACTION WITH SPRTN.
RX PubMed=23042607; DOI=10.1038/nsmb.2394;
RA Davis E.J., Lachaud C., Appleton P., Macartney T.J., Nathke I.,
RA Rouse J.;
RT "DVC1 (C1orf124) recruits the p97 protein segregase to sites of DNA
RT damage.";
RL Nat. Struct. Mol. Biol. 19:1093-1100(2012).
RN [44]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH SPRTN.
RX PubMed=23042605; DOI=10.1038/nsmb.2395;
RA Mosbech A., Gibbs-Seymour I., Kagias K., Thorslund T., Beli P.,
RA Povlsen L., Nielsen S.V., Smedegaard S., Sedgwick G., Lukas C.,
RA Hartmann-Petersen R., Lukas J., Choudhary C., Pocock R.,
RA Bekker-Jensen S., Mailand N.;
RT "DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes
RT ubiquitin-dependent responses to replication blocks.";
RL Nat. Struct. Mol. Biol. 19:1084-1092(2012).
RN [45]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1-481 IN COMPLEX WITH ATP
RP ANALOG, CHARACTERIZATION OF VARIANTS IBMPFD1 GLY-95 AND HIS-155,
RP MUTAGENESIS OF ARG-53 AND ARG-86, AND SUBUNIT.
RX PubMed=20512113; DOI=10.1038/emboj.2010.104;
RA Tang W.K., Li D., Li C.C., Esser L., Dai R., Guo L., Xia D.;
RT "A novel ATP-dependent conformation in p97 N-D1 fragment revealed by
RT crystal structures of disease-related mutants.";
RL EMBO J. 29:2217-2229(2010).
RN [46]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 797-806 IN COMPLEX WITH PLAA.
RX PubMed=19887378; DOI=10.1074/jbc.M109.044685;
RA Qiu L., Pashkova N., Walker J.R., Winistorfer S., Allali-Hassani A.,
RA Akutsu M., Piper R., Dhe-Paganon S.;
RT "Structure and function of the PLAA/Ufd3-p97/Cdc48 complex.";
RL J. Biol. Chem. 285:365-372(2010).
RN [47]
RP VARIANTS IBMPFD1 GLY-95; CYS-155; HIS-155; PRO-155; GLN-191 AND
RP GLU-232.
RX PubMed=15034582; DOI=10.1038/ng1332;
RA Watts G.D.J., Wymer J., Kovach M.J., Mehta S.G., Mumm S., Darvish D.,
RA Pestronk A., Whyte M.P., Kimonis V.E.;
RT "Inclusion body myopathy associated with Paget disease of bone and
RT frontotemporal dementia is caused by mutant valosin-containing
RT protein.";
RL Nat. Genet. 36:377-381(2004).
RN [48]
RP VARIANT IBMPFD1 CYS-155.
RX PubMed=15732117; DOI=10.1002/ana.20407;
RA Schroeder R., Watts G.D.J., Mehta S.G., Evert B.O., Broich P.,
RA Fliessbach K., Pauls K., Hans V.H., Kimonis V., Thal D.R.;
RT "Mutant valosin-containing protein causes a novel type of
RT frontotemporal dementia.";
RL Ann. Neurol. 57:457-461(2005).
RN [49]
RP VARIANT IBMPFD1 HIS-159.
RX PubMed=16247064; DOI=10.1212/01.wnl.0000180407.15369.92;
RA Haubenberger D., Bittner R.E., Rauch-Shorny S., Zimprich F.,
RA Mannhalter C., Wagner L., Mineva I., Vass K., Auff E., Zimprich A.;
RT "Inclusion body myopathy and Paget disease is linked to a novel
RT mutation in the VCP gene.";
RL Neurology 65:1304-1305(2005).
RN [50]
RP CHARACTERIZATION OF VARIANTS IBMPFD1 GLY-95 AND HIS-155.
RX PubMed=16321991; DOI=10.1093/hmg/ddi426;
RA Weihl C.C., Dalal S., Pestronk A., Hanson P.I.;
RT "Inclusion body myopathy-associated mutations in p97/VCP impair
RT endoplasmic reticulum-associated degradation.";
RL Hum. Mol. Genet. 15:189-199(2006).
RN [51]
RP VARIANTS ALS14 HIS-155; GLY-159; GLN-191 AND ASN-592.
RX PubMed=21145000; DOI=10.1016/j.neuron.2010.11.036;
RA Johnson J.O., Mandrioli J., Benatar M., Abramzon Y., Van Deerlin V.M.,
RA Trojanowski J.Q., Gibbs J.R., Brunetti M., Gronka S., Wuu J., Ding J.,
RA McCluskey L., Martinez-Lage M., Falcone D., Hernandez D.G.,
RA Arepalli S., Chong S., Schymick J.C., Rothstein J., Landi F.,
RA Wang Y.D., Calvo A., Mora G., Sabatelli M., Monsurro M.R.,
RA Battistini S., Salvi F., Spataro R., Sola P., Borghero G., Galassi G.,
RA Scholz S.W., Taylor J.P., Restagno G., Chio A., Traynor B.J.;
RT "Exome sequencing reveals VCP mutations as a cause of familial ALS.";
RL Neuron 68:857-864(2010).
CC -!- FUNCTION: Necessary for the fragmentation of Golgi stacks during
CC mitosis and for their reassembly after mitosis. Involved in the
CC formation of the transitional endoplasmic reticulum (tER). The
CC transfer of membranes from the endoplasmic reticulum to the Golgi
CC apparatus occurs via 50-70 nm transition vesicles which derive
CC from part-rough, part-smooth transitional elements of the
CC endoplasmic reticulum (tER). Vesicle budding from the tER is an
CC ATP-dependent process. The ternary complex containing UFD1L, VCP
CC and NPLOC4 binds ubiquitinated proteins and is necessary for the
CC export of misfolded proteins from the ER to the cytoplasm, where
CC they are degraded by the proteasome. The NPLOC4-UFD1L-VCP complex
CC regulates spindle disassembly at the end of mitosis and is
CC necessary for the formation of a closed nuclear envelope.
CC Regulates E3 ubiquitin-protein ligase activity of RNF19A (By
CC similarity). Component of the VCP/p97-AMFR/gp78 complex that
CC participates in the final step of the sterol-mediated
CC ubiquitination and endoplasmic reticulum-associated degradation
CC (ERAD) of HMGCR. Also involved in DNA damage response: recruited
CC to double-strand breaks (DSBs) sites in a RNF8- and RNF168-
CC dependent manner and promotes the recruitment of TP53BP1 at DNA
CC damage sites. Recruited to stalled replication forks by SPRTN: may
CC act by mediating extraction of DNA polymerase eta (POLH) to
CC prevent excessive translesion DNA synthesis and limit the
CC incidence of mutations induced by DNA damage.
CC -!- CATALYTIC ACTIVITY: ATP + H(2)O = ADP + phosphate.
CC -!- SUBUNIT: Homohexamer. Forms a ring-shaped particle of 12.5 nm
CC diameter, that displays 6-fold radial symmetry. Part of a ternary
CC complex containing STX5A, NSFL1C and VCP. NSFL1C forms a
CC homotrimer that binds to one end of a VCP homohexamer. The complex
CC binds to membranes enriched in phosphatidylethanolamine-containing
CC lipids and promotes Golgi membrane fusion. Binds to a heterodimer
CC of NPLOC4 and UFD1L, binding to this heterodimer inhibits Golgi-
CC membrane fusion. Interaction with VCIP135 leads to dissociation of
CC the complex via ATP hydrolysis by VCP. Part of a ternary complex
CC containing NPLOC4, UFD1L and VCP. Interacts with NSFL1C-like
CC protein p37; the complex has membrane fusion activity and is
CC required for Golgi and endoplasmic reticulum biogenesis (By
CC similarity). Interacts with VIMP/SELS and SYVN1, as well as with
CC DERL1, DERL2 and DERL3; which probably transfer misfolded proteins
CC from the ER to VCP. Interacts with SVIP. Component of a complex
CC required to couple retrotranslocation, ubiquitination and
CC deglycosylation composed of NGLY1, SAKS1, AMFR, VCP and RAD23B.
CC Directly interacts with UBXD2 and RNF19A. Interacts with CASR.
CC Interacts with UBXN6, UBE4B and YOD1. Interacts with clathrin.
CC Interacts with RNF103. Interacts with TRIM13 and TRIM21. Component
CC of a VCP/p97-AMFR/gp78 complex that participates in the final step
CC of the endoplasmic reticulum-associated degradation (ERAD) of
CC HMGCR. Interacts directly with AMFR/gp78 (via its VIM). Interacts
CC with RHBDD1 (via C-terminus domain). Interacts with SPRTN; leading
CC to recruitment to stalled replication forks.
CC -!- INTERACTION:
CC Q9UKV5:AMFR; NbExp=6; IntAct=EBI-355164, EBI-1046367;
CC Q9BZE9:ASPSCR1; NbExp=3; IntAct=EBI-355164, EBI-1993677;
CC P54252:ATXN3; NbExp=8; IntAct=EBI-355164, EBI-946046;
CC P54252-1:ATXN3; NbExp=10; IntAct=EBI-355164, EBI-946068;
CC O96017:CHEK2; NbExp=2; IntAct=EBI-355164, EBI-1180783;
CC O94868:FCHSD2; NbExp=2; IntAct=EBI-355164, EBI-1215612;
CC Q9UNZ2:NSFL1C; NbExp=4; IntAct=EBI-355164, EBI-721577;
CC P26045:PTPN3; NbExp=2; IntAct=EBI-355164, EBI-1047946;
CC B1AQ61:UBE4B; NbExp=4; IntAct=EBI-355164, EBI-7931266;
CC Q92575:UBXN4; NbExp=2; IntAct=EBI-355164, EBI-723441;
CC Q9BZV1:UBXN6; NbExp=7; IntAct=EBI-355164, EBI-1993899;
CC P63104:YWHAZ; NbExp=2; IntAct=EBI-355164, EBI-347088;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol. Endoplasmic reticulum.
CC Nucleus. Note=Present in the neuronal hyaline inclusion bodies
CC specifically found in motor neurons from amyotrophic lateral
CC sclerosis patients. Present in the Lewy bodies specifically found
CC in neurons from Parkinson disease patients. Recruited to the
CC cytoplasmic surface of the endoplasmic reticulum via interaction
CC with AMFR/gp78. Following DNA double-strand breaks, recruited to
CC the sites of damage. Recruited to stalled replication forks via
CC interaction with SPRTN.
CC -!- PTM: Phosphorylated by tyrosine kinases in response to T-cell
CC antigen receptor activation (By similarity).
CC -!- PTM: ISGylated.
CC -!- PTM: Methylation at Lys-315 catalyzed by VCPKMT is increased in
CC the presence of ASPSCR1. Lys-315 methylation may decrease ATPase
CC activity.
CC -!- DISEASE: Inclusion body myopathy with early-onset Paget disease
CC with or without frontotemporal dementia 1 (IBMPFD1) [MIM:167320]:
CC An autosomal dominant disease characterized by disabling muscle
CC weakness clinically resembling to limb girdle muscular dystrophy,
CC osteolytic bone lesions consistent with Paget disease, and
CC premature frontotemporal dementia. Clinical features show
CC incomplete penetrance. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Amyotrophic lateral sclerosis 14, with or without
CC frontotemporal dementia (ALS14) [MIM:613954]: A neurodegenerative
CC disorder affecting upper motor neurons in the brain and lower
CC motor neurons in the brain stem and spinal cord, resulting in
CC fatal paralysis. Sensory abnormalities are absent. The pathologic
CC hallmarks of the disease include pallor of the corticospinal tract
CC due to loss of motor neurons, presence of ubiquitin-positive
CC inclusions within surviving motor neurons, and deposition of
CC pathologic aggregates. The etiology of amyotrophic lateral
CC sclerosis is likely to be multifactorial, involving both genetic
CC and environmental factors. The disease is inherited in 5-10% of
CC the cases. Patients with ALS14 may develop frontotemporal
CC dementia. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the AAA ATPase family.
CC -!- CAUTION: It is unclear how it participates in the recruitment of
CC TP53BP1 at DNA damage sites. According to a first report,
CC participates in the recruitment of TP53BP1 by promoting
CC ubiquitination and removal of L3MBTL1 from DNA damage sites
CC (PubMed:22120668). According to a second report, it acts by
CC removing 'Lys-48'-linked ubiquitination from sites of DNA damage
CC (PubMed:22020440).
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/VCP";
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DR EMBL; AC004472; AAC07984.1; -; Genomic_DNA.
DR EMBL; AF100752; AAD43016.1; -; mRNA.
DR EMBL; AK312310; BAG35235.1; -; mRNA.
DR EMBL; AL353795; CAH70993.1; -; Genomic_DNA.
DR EMBL; CH471071; EAW58404.1; -; Genomic_DNA.
DR EMBL; BC110913; AAI10914.1; -; mRNA.
DR EMBL; BC121794; AAI21795.1; -; mRNA.
DR EMBL; Z70768; CAA94809.1; -; mRNA.
DR PIR; T02243; T02243.
DR RefSeq; NP_009057.1; NM_007126.3.
DR UniGene; Hs.529782; -.
DR PDB; 3EBB; X-ray; 1.90 A; E/F/G/H=797-806.
DR PDB; 3HU1; X-ray; 2.81 A; A/B/C/D/E/F=1-481.
DR PDB; 3HU2; X-ray; 2.85 A; A/B/C/D/E/F=1-481.
DR PDB; 3HU3; X-ray; 2.20 A; A/B=1-481.
DR PDB; 3QC8; X-ray; 2.20 A; A=21-196.
DR PDB; 3QQ7; X-ray; 2.65 A; A=2-187.
DR PDB; 3QQ8; X-ray; 2.00 A; A=2-187.
DR PDB; 3QWZ; X-ray; 2.00 A; A=1-208.
DR PDB; 3TIW; X-ray; 1.80 A; A/B=1-187.
DR PDB; 4KLN; X-ray; 2.62 A; A/B/C/D/E/F=1-481.
DR PDB; 4KO8; X-ray; 1.98 A; A/B=1-481.
DR PDB; 4KOD; X-ray; 2.96 A; A/B/C/D/E/F/G/H/I/J/K/L=1-481.
DR PDBsum; 3EBB; -.
DR PDBsum; 3HU1; -.
DR PDBsum; 3HU2; -.
DR PDBsum; 3HU3; -.
DR PDBsum; 3QC8; -.
DR PDBsum; 3QQ7; -.
DR PDBsum; 3QQ8; -.
DR PDBsum; 3QWZ; -.
DR PDBsum; 3TIW; -.
DR PDBsum; 4KLN; -.
DR PDBsum; 4KO8; -.
DR PDBsum; 4KOD; -.
DR ProteinModelPortal; P55072; -.
DR SMR; P55072; 10-763.
DR DIP; DIP-33543N; -.
DR IntAct; P55072; 55.
DR MINT; MINT-272884; -.
DR STRING; 9606.ENSP00000351777; -.
DR BindingDB; P55072; -.
DR ChEMBL; CHEMBL1075145; -.
DR TCDB; 3.A.16.1.1; the endoplasmic reticular retrotranslocon (er-rt) family.
DR PhosphoSite; P55072; -.
DR DMDM; 6094447; -.
DR DOSAC-COBS-2DPAGE; P55072; -.
DR OGP; P55072; -.
DR REPRODUCTION-2DPAGE; IPI00022774; -.
DR REPRODUCTION-2DPAGE; P55072; -.
DR PaxDb; P55072; -.
DR PRIDE; P55072; -.
DR Ensembl; ENST00000358901; ENSP00000351777; ENSG00000165280.
DR GeneID; 7415; -.
DR KEGG; hsa:7415; -.
DR UCSC; uc003zvy.2; human.
DR CTD; 7415; -.
DR GeneCards; GC09M035056; -.
DR HGNC; HGNC:12666; VCP.
DR HPA; CAB005593; -.
DR HPA; HPA012728; -.
DR HPA; HPA012814; -.
DR MIM; 167320; phenotype.
DR MIM; 601023; gene.
DR MIM; 613954; phenotype.
DR neXtProt; NX_P55072; -.
DR Orphanet; 329478; Adult-onset distal myopathy due to VCP mutation.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR Orphanet; 52430; Inclusion body myopathy with Paget disease of bone and frontotemporal dementia.
DR Orphanet; 329475; Spastic paraplegia - Paget disease of bone.
DR PharmGKB; PA37289; -.
DR eggNOG; COG0464; -.
DR HOGENOM; HOG000223224; -.
DR HOVERGEN; HBG001226; -.
DR InParanoid; P55072; -.
DR KO; K13525; -.
DR OMA; DKFLKYG; -.
DR OrthoDB; EOG7H4DSW; -.
DR SignaLink; P55072; -.
DR ChiTaRS; VCP; human.
DR EvolutionaryTrace; P55072; -.
DR GeneWiki; Valosin-containing_protein; -.
DR GenomeRNAi; 7415; -.
DR NextBio; 29034; -.
DR PRO; PR:P55072; -.
DR ArrayExpress; P55072; -.
DR Bgee; P55072; -.
DR CleanEx; HS_VCP; -.
DR Genevestigator; P55072; -.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0005811; C:lipid particle; IDA:MGI.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0000502; C:proteasome complex; IDA:BHF-UCL.
DR GO; GO:0035861; C:site of double-strand break; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0016887; F:ATPase activity; TAS:UniProtKB.
DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW.
DR GO; GO:0031593; F:polyubiquitin binding; IDA:BHF-UCL.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; ISS:UniProtKB.
DR GO; GO:0006302; P:double-strand break repair; IDA:UniProtKB.
DR GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; TAS:UniProtKB.
DR GO; GO:0030433; P:ER-associated ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IDA:BHF-UCL.
DR GO; GO:0031334; P:positive regulation of protein complex assembly; IDA:BHF-UCL.
DR GO; GO:0018279; P:protein N-linked glycosylation via asparagine; IMP:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; IDA:UniProtKB.
DR GO; GO:0030970; P:retrograde protein transport, ER to cytosol; IDA:UniProtKB.
DR GO; GO:0019985; P:translesion synthesis; IMP:UniProtKB.
DR InterPro; IPR003593; AAA+_ATPase.
DR InterPro; IPR005938; AAA_ATPase_CDC48.
DR InterPro; IPR009010; Asp_de-COase-like_dom.
DR InterPro; IPR003959; ATPase_AAA_core.
DR InterPro; IPR003960; ATPase_AAA_CS.
DR InterPro; IPR004201; Cdc48_dom2.
DR InterPro; IPR003338; CDC4_N-term_subdom.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR015415; Vps4_C.
DR Pfam; PF00004; AAA; 2.
DR Pfam; PF02933; CDC48_2; 1.
DR Pfam; PF02359; CDC48_N; 1.
DR Pfam; PF09336; Vps4_C; 1.
DR SMART; SM00382; AAA; 2.
DR SMART; SM01072; CDC48_2; 1.
DR SMART; SM01073; CDC48_N; 1.
DR SUPFAM; SSF50692; SSF50692; 1.
DR SUPFAM; SSF52540; SSF52540; 2.
DR TIGRFAMs; TIGR01243; CDC48; 1.
DR PROSITE; PS00674; AAA; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Amyotrophic lateral sclerosis; ATP-binding;
KW Complete proteome; Cytoplasm; Direct protein sequencing;
KW Disease mutation; DNA damage; DNA repair; Endoplasmic reticulum;
KW Hydrolase; Lipid-binding; Methylation; Neurodegeneration;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Transport; Ubl conjugation; Ubl conjugation pathway.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 806 Transitional endoplasmic reticulum
FT ATPase.
FT /FTId=PRO_0000084572.
FT NP_BIND 247 253 ATP.
FT REGION 797 806 Interaction with UBXN6.
FT BINDING 348 348 ATP.
FT BINDING 384 384 ATP.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 3 3 Phosphoserine.
FT MOD_RES 37 37 Phosphoserine.
FT MOD_RES 315 315 N6,N6,N6-trimethyllysine; by VCPKMT.
FT MOD_RES 436 436 Phosphothreonine.
FT MOD_RES 770 770 Phosphoserine.
FT MOD_RES 775 775 Phosphoserine.
FT MOD_RES 787 787 Phosphoserine.
FT MOD_RES 805 805 Phosphotyrosine (By similarity).
FT VARIANT 95 95 R -> G (in IBMPFD1; cultured cells
FT expressing the mutant protein show a
FT marked general increase in the level of
FT ubiquitin-conjugated proteins and
FT impaired protein degradation through the
FT endoplasmic reticulum-associated
FT degradation (ERAD) pathway; shows
FT strongly reduced affinity for ADP and
FT increased affinity for ATP; abolishes
FT enhancement of K-315 methylation by
FT ASPSCR1).
FT /FTId=VAR_033016.
FT VARIANT 155 155 R -> C (in IBMPFD1; also in one patient
FT without evidence of Paget disease of the
FT bone).
FT /FTId=VAR_033017.
FT VARIANT 155 155 R -> H (in ALS14 and IBMPFD1; ALS14
FT patients do not manifest frontotemporal
FT dementia; properly assembles into a
FT hexameric structure and shows normal
FT ATPase activity; cultured cells
FT expressing the mutant protein show a
FT marked general increase in the level of
FT ubiquitin-conjugated proteins and
FT impaired protein degradation through the
FT endoplasmic reticulum-associated
FT degradation (ERAD) pathway; shows
FT strongly reduced affinity for ADP and
FT increased affinity for ATP).
FT /FTId=VAR_033018.
FT VARIANT 155 155 R -> P (in IBMPFD1).
FT /FTId=VAR_033019.
FT VARIANT 159 159 R -> G (in ALS14).
FT /FTId=VAR_065910.
FT VARIANT 159 159 R -> H (in IBMPFD1; without
FT frontotemporal dementia; abolishes
FT enhancement of K-315 methylation by
FT ASPSCR1).
FT /FTId=VAR_033020.
FT VARIANT 191 191 R -> Q (in ALS14 and IBMPFD1; abolishes
FT enhancement of K-315 methylation by
FT ASPSCR1).
FT /FTId=VAR_033021.
FT VARIANT 232 232 A -> E (in IBMPFD1).
FT /FTId=VAR_033022.
FT VARIANT 592 592 D -> N (in ALS14; ALS14 patients do not
FT show frontotemporal dementia).
FT /FTId=VAR_065911.
FT MUTAGEN 53 53 R->A: Minor effect on affinity for ATP
FT and ADP.
FT MUTAGEN 86 86 R->A: Strongly increased affinity for
FT ATP. Strongly reduced affinity for ADP.
FT MUTAGEN 251 251 K->Q: Impairs ERAD degradation of HMGCR
FT and does not inhibit interaction with
FT RHBDD1; when associated with Q-524.
FT MUTAGEN 312 312 K->A: Does not affect methylation by
FT VCPKMT.
FT MUTAGEN 313 313 R->A: Does not affect methylation by
FT VCPKMT.
FT MUTAGEN 314 314 E->A: Does not affect methylation by
FT VCPKMT.
FT MUTAGEN 314 314 Missing: Strongly impairs methylation by
FT VCPKMT.
FT MUTAGEN 315 315 K->L,Q,R: Abolishes methylation by
FT VCPKMT.
FT MUTAGEN 316 316 T->A: Does not affect methylation by
FT VCPKMT.
FT MUTAGEN 317 317 H->A: Does not affect methylation by
FT VCPKMT.
FT MUTAGEN 318 318 G->A: Does not affect methylation by
FT VCPKMT.
FT MUTAGEN 524 524 K->A: Impairs catalytic activity of
FT RNF19A toward SOD1 mutant. Does not
FT inhibit interaction with RHBDD1; when
FT associated with A-251.
FT MUTAGEN 524 524 K->Q: Impairs ERAD degradation of HMGCR;
FT when associated with Q-251.
FT MUTAGEN 578 578 E->Q: Does not inhibit interaction with
FT RHBDD1.
FT CONFLICT 169 169 D -> H (in Ref. 6; AAI21795).
FT CONFLICT 312 312 K -> I (in Ref. 3; BAG35235).
FT HELIX 14 17
FT STRAND 25 30
FT STRAND 38 41
FT HELIX 43 49
FT STRAND 56 60
FT HELIX 62 64
FT STRAND 66 73
FT STRAND 75 77
FT STRAND 81 84
FT HELIX 86 91
FT STRAND 99 104
FT STRAND 112 118
FT HELIX 120 122
FT HELIX 123 126
FT HELIX 130 133
FT HELIX 135 139
FT TURN 140 142
FT STRAND 145 147
FT STRAND 151 155
FT STRAND 157 175
FT STRAND 181 183
FT HELIX 193 195
FT HELIX 203 205
FT HELIX 210 219
FT HELIX 221 225
FT HELIX 227 233
FT STRAND 240 244
FT HELIX 251 261
FT STRAND 263 270
FT HELIX 271 275
FT HELIX 281 295
FT STRAND 298 305
FT HELIX 306 309
FT STRAND 313 315
FT HELIX 319 334
FT HELIX 337 339
FT STRAND 341 348
FT HELIX 350 352
FT HELIX 355 358
FT STRAND 365 368
FT HELIX 374 384
FT TURN 385 387
FT HELIX 396 401
FT HELIX 408 424
FT TURN 425 429
FT STRAND 432 436
FT HELIX 439 444
FT HELIX 449 456
FT HELIX 459 465
FT HELIX 466 468
SQ SEQUENCE 806 AA; 89322 MW; 501B721D3A77BA8A CRC64;
MASGADSKGD DLSTAILKQK NRPNRLIVDE AINEDNSVVS LSQPKMDELQ LFRGDTVLLK
GKKRREAVCI VLSDDTCSDE KIRMNRVVRN NLRVRLGDVI SIQPCPDVKY GKRIHVLPID
DTVEGITGNL FEVYLKPYFL EAYRPIRKGD IFLVRGGMRA VEFKVVETDP SPYCIVAPDT
VIHCEGEPIK REDEEESLNE VGYDDIGGCR KQLAQIKEMV ELPLRHPALF KAIGVKPPRG
ILLYGPPGTG KTLIARAVAN ETGAFFFLIN GPEIMSKLAG ESESNLRKAF EEAEKNAPAI
IFIDELDAIA PKREKTHGEV ERRIVSQLLT LMDGLKQRAH VIVMAATNRP NSIDPALRRF
GRFDREVDIG IPDATGRLEI LQIHTKNMKL ADDVDLEQVA NETHGHVGAD LAALCSEAAL
QAIRKKMDLI DLEDETIDAE VMNSLAVTMD DFRWALSQSN PSALRETVVE VPQVTWEDIG
GLEDVKRELQ ELVQYPVEHP DKFLKFGMTP SKGVLFYGPP GCGKTLLAKA IANECQANFI
SIKGPELLTM WFGESEANVR EIFDKARQAA PCVLFFDELD SIAKARGGNI GDGGGAADRV
INQILTEMDG MSTKKNVFII GATNRPDIID PAILRPGRLD QLIYIPLPDE KSRVAILKAN
LRKSPVAKDV DLEFLAKMTN GFSGADLTEI CQRACKLAIR ESIESEIRRE RERQTNPSAM
EVEEDDPVPE IRRDHFEEAM RFARRSVSDN DIRKYEMFAQ TLQQSRGFGS FRFPSGNQGG
AGPSQGSGGG TGGSVYTEDN DDDLYG
//
MIM
167320
*RECORD*
*FIELD* NO
167320
*FIELD* TI
#167320 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE WITH OR WITHOUT
FRONTOTEMPORAL DEMENTIA 1; IBMPFD1
read more;;MULTISYSTEM PROTEINOPATHY 1; MSP1;;
MUSCULAR DYSTROPHY, LIMB-GIRDLE, WITH PAGET DISEASE OF BONE;;
PAGETOID AMYOTROPHIC LATERAL SCLEROSIS;;
PAGETOID NEUROSKELETAL SYNDROME;;
LOWER MOTOR NEURON DEGENERATION WITH PAGET-LIKE BONE DISEASE
*FIELD* TX
A number sign (#) is used with this entry because inclusion body
myopathy with Paget disease and frontotemporal dementia (IBMPFD1) is
caused by mutation in valosin-containing protein (VCP; 601023).
See also amyotrophic lateral sclerosis-14 with or without frontotemporal
dementia (ALS14; 613954), which is also caused by heterozygous mutation
in the VCP gene and can show overlapping clinical features.
DESCRIPTION
IBMPFD is an autosomal dominant disorder characterized by incomplete
penetrance of 3 main features: disabling muscle weakness (in 90%),
osteolytic bone lesions consistent with Paget disease (in 51%), and
frontotemporal dementia (in 32%).
Weihl et al. (2009) presented a detailed review of the disorder.
Importantly, muscle weakness is an isolated symptom in about 30% of
patients, and is the presenting symptom in greater than half of
patients, suggesting that IBMPFD may be commonly seen in a neuromuscular
clinic without its other syndromic features.
- Genetic Heterogeneity of IBMPFD
IBMPFD2 (615422) is caused by mutation in the HNRNPA2B1 gene (600124) on
chromosome 7p15. IBMPFD3 (615424) is caused by mutation in the HNRNPA1
gene (164017) on chromosome 12q13.
CLINICAL FEATURES
Tucker et al. (1982) studied a large kindred with a syndrome of lower
motor neuron degeneration and polyostotic skeletal disorganization
resembling Paget disease of bone (PDB; 602080). The disorder begins
insidiously at about age 35 with weakness and atrophy of the leg and
proximal arm muscles. Nerve conductions are normal; EMG shows muscle
denervation, as does muscle biopsy. The disorder progresses to
wheelchair confinement and later to bed confinement, quadriparesis,
dementia, respiratory failure, and death before age 60 years. Even early
in the neurologic illness, patients have coarse trabeculation, cortical
thickening, and spotty sclerosis on bone x-rays; diffusely increased
uptake of radionuclide and elevated heat-labile serum alkaline
phosphatase. The disorder affected 6 females and 6 males in 5 sibships
of 3 generations with no instance of male-to-male transmission.
Kimonis et al. (2000) described a family in which autosomal dominant
limb-girdle muscular dystrophy (LGMD) was associated with early-onset
Paget disease of bone PDB and cardiomyopathy. Eight of 11 affected
individuals had both disorders. Onset of PDB occurred at a mean age of
35 years, with classic distribution involving the spine, pelvis, and
skull. Muscle weakness and atrophy was progressive with mildly elevated
to normal CPK levels. Muscle biopsy in the oldest male revealed
vacuolated fibers, but in others revealed nonspecific myopathy. Affected
individuals die from progressive muscle weakness and respiratory and
cardiac failure in their forties to sixties.
Kovach et al. (2001) described the clinical, biochemical, radiologic,
and pathologic characteristics of 49 affected individuals from the
family described by Kimonis et al. (2000) and 3 other unrelated families
with autosomal dominant inclusion body myopathy (IBM), PDB, and
frontotemporal dementia. Ninety percent of the patients had myopathy,
43% had PDB, and 37% had premature frontotemporal dementia.
Watts et al. (2004) reported 13 families with IBMPFD, 12 from the U.S.
and 1 from Canada. Among those individuals, 82% of affected individuals
had myopathy, 49% had PDB, and 30% had early-onset frontotemporal
dementia. The mean age at presentation was 42 years for both IBM and
PDB, whereas frontotemporal dementia typically presented at age 53
years. In IBMPFD myopathic muscle and PDB osteoclasts, inclusions appear
similar, suggestive of disruptions in the same pathologic pathway.
Family 11 in the report by Watts et al. (2004) was originally reported
by Tucker et al. (1982) (Kimonis, 2005).
Haubenberger et al. (2005) reported an Austrian family in which 4 sibs
had autosomal dominant inclusion body myopathy and Paget disease
associated with a heterozygous mutation in the VCP gene (R159H;
601023.0007). None of the affected individuals developed frontotemporal
dementia even though all were over 60 years of age. Haubenberger et al.
(2005) noted that only approximately 30% of patients with VCP mutations
develop dementia, illustrating phenotypic variability. In a follow-up of
this family, van der Zee et al. (2009) noted that 1 patient had
developed dementia at age 64. Van der Zee et al. (2009) also identified
the R159H mutation in affected members of 2 unrelated Belgian families.
In 1 family, patients presented with frontotemporal lobar degeneration
only, whereas in the other family, patients developed frontotemporal
lobar degeneration, Paget disease of the bone, or both without signs of
inclusion body myopathy for any of the mutation carriers. Haplotype
analysis showed that the 2 families and the Austrian family reported by
Haubenberger et al. (2005) were unrelated. Autopsy data of 3 patients
from the 2 Belgian families showed frontotemporal lobar degeneration
with numerous ubiquitin-immunoreactive, intranuclear inclusions and
dystrophic neurites staining positive for TDP43 (TARDBP; 605078)
protein. Van der Zee et al. (2009) commented on the high degree of
clinical heterogeneity and incomplete penetrance of the disorder in
different families carrying the same mutation.
Kimonis et al. (2008) reported detailed clinical features of 49 patients
from 9 families with IBMPFD confirmed by genetic analysis. One family
had been previously reported by Tucker et al. (1982). Forty-two (86%)
patients had muscle disease, the majority of whom were initially
misdiagnosed as having some other form of muscular dystrophy or spinal
muscular atrophy. Weakness was distal and/or proximal, and many patients
were confined to wheelchairs. Muscle biopsies showed inclusion bodies
and/or rimmed vacuoles (39%) or nonspecific changes. Frontotemporal
dementia was diagnosed in 13 (27%) of 49 individuals at a mean age of 57
years, of whom 3 had been originally diagnosed with Alzheimer disease
(104300). Paget disease of bone was found in 28 (57%) of 49 patients at
a mean age of 40 years and correlated with increased serum alkaline
phosphatase. Kimonis et al. (2008) postulated that IBMPFD is
underdiagnosed among patients with myopathy and/or dementia.
Viassolo et al. (2008) reported an Italian family in which 2 sibs and
their mother had IBMPFD. All 3 had progressive inclusion body myopathy
and rapidly progressive severe dementia, but only 1 developed Paget
disease. Genetic analysis identified a heterozygous mutation in the VCP
gene (R155H; 601023.0001). Several other family members were reportedly
affected. Viassolo et al.(2008) discussed the implications of the
incomplete penetrance of some of the features for genetic counseling.
Kim et al. (2011) reported 3 Korean sibs with IBMPFD confirmed by
genetic analysis (601023.0002). The proband developed progressive
dementia presenting as fluent aphasia and language difficulties with
onset at age 47. She never developed myopathy, but did develop
asymptomatic Paget disease with increased serum alkaline phosphatase and
lytic bone lesions on imaging. Her brother developed slowly progressive
proximal muscle weakness at age 50, followed by frontotemporal dementia
characterized initially by comprehension defects at age 54. He never had
Paget disease, although serum alkaline phosphatase was increased. A
second brother developed muscle weakness at age 47, followed by Paget
disease at age 53, and dementia at age 61. Brain MRI in all patients
showed asymmetric atrophy in the anterior inferior and lateral temporal
lobes and inferior parietal lobule with ventricular dilatation on the
affected side (2 on the left, 1 on the right). Two had glucose
hypometabolism in the lateral temporal and inferior parietal areas, with
less involvement of the anterior temporal and frontal lobes compared to
those with typical semantic dementia.
Sacconi et al. (2012) reported 2 unrelated men in their fifties who
presented with a phenotype reminiscent of FSHD1 (158900) but were found
to carry a heterozygous VCP mutation (R191Q; 601023.0006). One had
scapuloperoneal weakness without facial involvement and increased serum
creatine kinase. The second patient had facial weakness, shoulder and
pelvic girdle weakness, and anterior foreleg weakness. Creatine kinase
was increased 4-fold. Muscle biopsies of both patients showed mild
dystrophic changes, but no inclusion bodies. Both had a myopathic
pattern on EMG. One was later found to have a mild dysexecutive
syndrome, but neither had evidence of Paget disease.
- Neuropathologic Findings
Schroder et al. (2005) reported a patient with frontotemporal dementia
(FTD) and inclusion body myopathy caused by mutation in the VCP gene
(601023.0002). There was no evidence of Paget disease. Neuropathologic
examination showed cortical atrophy and widespread neuronal loss;
subcortical neuronal loss was less severe. The cerebral and cerebellar
white matter had severe astrogliosis. Surviving cortical pyramidal
neurons contained VCP- and ubiquitin (see 191321)-positive intranuclear
inclusions and displayed cytoplasmic autofluorescence consistent with
lipofuscin. Nuclear inclusions were not seen in astrocytes,
oligodendrocytes, or microglial cells. Western blot analysis showed a
single 97-kD band corresponding to normal-sized VCP that was similar to
control brains. Schroder et al. (2005) concluded that mutant VCP causes
a novel form of frontotemporal dementia, distinct from tau (MAPT;
157140)-associated FTD (see 600274), characterized by neuronal nuclear
inclusions containing ubiquitin and VCP. The authors suggested that
mutant VCP interferes with ubiquitin-dependent pathways, leading to
abnormal intracellular and intranuclear protein aggregation.
MAPPING
In a family with autosomal dominant LGMD associated with early-onset PDB
and cardiomyopathy, Kimonis et al. (2000) excluded autosomal dominant
and recessive LGMD, PDB, and cardiomyopathy loci. They argued that their
linkage analysis data indicated a unique locus in this family.
By linkage analysis, Kovach et al. (2001) localized autosomal dominant
IBM with PDB and frontotemporal dementia to a 1.08- to 6.46-cM critical
interval on 9p13.3-p12 in the region of autosomal recessive IBM2
(600737). The maximum lod score generated from the combined genotype
data was 9.29 for marker D91791.
MOLECULAR GENETICS
Watts et al. (2004) performed haplotype analysis of 13 families with
IBMPFD and identified 2 ancestral disease-associated haplotypes,
distinguishing families 1, 3, 7, and 16 (group A) from families 2 and 5
(group B). Both groups were of northern European ancestry. The
predominant IBMPFD haplotype of group A includes a core haplotype
flanked by D9S1118 and D9S234, probably transmitted from a shared
ancestor. Watts et al. (2004) identified 6 missense mutations in the
valosin-containing protein (VCP; 601023) in these families. Families 1,
3, 4, 7, 10, 15, and 16 shared the R155H mutation in exon 5
(601023.0001); families 2 and 5 had an R155C mutation (601023.0002); and
family 11 had an R155P mutation (601023.0005). Thus, 10 of the 13
families with IBMPFD had an amino acid change at codon 155 in VCP, which
therefore seems to be a mutation hotspot. In addition, 1 family had a
missense mutation at codon 232 (601023.0003), another at codon 95
(601023.0004), and another at codon 191 (601023.0006).
GENOTYPE/PHENOTYPE CORRELATIONS
Mehta et al. (2013) analyzed clinical and biochemical markers from a
database of 190 individuals from 27 families harboring 10 missense
mutations in the VCP gene. Among these, 145 mutation carriers were
symptomatic and 45 were presymptomatic. The most common clinical feature
(in 91% of patients) was onset of myopathic weakness at a mean age of 43
years. Paget disease of the bone was found in 52% of patients at a mean
age of 41 years. Frontotemporal dementia occurred in 30% of patients at
a mean age of 55 years. Significant genotype-phenotype correlations were
difficult to establish because of small numbers. However, patients with
the R155C mutation had a more severe phenotype with an earlier onset of
myopathy and Paget disease, as well as decreased survival, compared to
those with the R155H mutation. A diagnosis of ALS was found in at least
13 (8.9%) individuals from the 27 families, including 10 patients with
the R155H mutation, and 5 (3%) patients were diagnosed with Parkinson
disease.
NOMENCLATURE
IBMPFD may also be referred to as FTLD-TDP (or TDP43), VCP-related,
based on neuropathologic findings (MacKenzie et al., 2010).
ANIMAL MODEL
Weihl et al. (2007) found that transgenic mice overexpressing the R155H
mutation became progressively weaker in a dose-dependent manner starting
at 6 months of age. There was abnormal muscle pathology, with coarse
internal architecture, vacuolation and disorganized membrane morphology
with reduced caveolin-3 (CAV3; 601253) expression at the sarcolemma.
Even before animals displayed measurable weakness, there was an increase
in ubiquitin-containing protein inclusions and high molecular weight
ubiquitinated proteins. These findings suggested a dysregulation in
protein degradation.
Custer et al. (2010) developed and characterized transgenic mice with
ubiquitous expression of wildtype and disease-causing versions of human
VCP/p97. Mice expressing VCP/p97 harboring the mutations R155H
(601023.0001) or A232E (601023.0003) exhibited progressive muscle
weakness, and developed inclusion body myopathy including rimmed
vacuoles and TDP43 pathology. The brain showed widespread TDP43 (605078)
pathology, and the skeleton exhibited severe osteopenia accompanied by
focal lytic and sclerotic lesions in vertebrae and femur. In vitro
studies indicated that mutant VCP caused inappropriate activation of the
NF-kappa-B (see 164011) signaling cascade, which could contribute to the
mechanism of pathogenesis in multiple tissues including muscle, bone,
and brain.
*FIELD* RF
1. Custer, S. K.; Neumann, M.; Lu, H.; Wright, A. C.; Taylor, J. P.
: Transgenic mice expressing mutant forms VCP/p97 recapitulate the
full spectrum of IBMPFD including degeneration in muscle, brain and
bone. Hum. Molec. Genet. 19: 1741-1755, 2010.
2. Haubenberger, D.; Bittner, R. E.; Rauch-Shorny, S.; Zimprich, F.;
Mannhalter, C.; Wagner, L.; Mineva, I.; Vass, K.; Auff, E.; Zimprich,
A.: Inclusion body myopathy and Paget disease is linked to a novel
mutation in the VCP gene. Neurology 65: 1304-1305, 2005.
3. Kim, E.-J.; Park, Y.-E.; Kim, D.-S.; Ahn, B.-Y.; Kim, H.-S.; Chang,
Y. H.; Kim, S.-J,; Kim, H.-J.; Lee, H.-W.; Seeley, W. W.; Kim, S.
: Inclusion body myopathy with Paget disease of bone and frontotemporal
dementia linked to VCP p.Arg155Cys in a Korean family. Arch. Neurol. 68:
787-796, 2011.
4. Kimonis, V. E.: Personal Communication. Boston, Mass. 1/12/2005.
5. Kimonis, V. E.; Kovach, M. J.; Waggoner, B.; Leal, S.; Salam, A.;
Rimer, L.; Davis, K.; Khardori, R.; Gelber, D.: Clinical and molecular
studies in a unique family with autosomal dominant limb-girdle muscular
dystrophy and Paget disease of bone. Genet. Med. 2: 232-241, 2000.
6. Kimonis, V. E.; Mehta, S. G.; Fulchiero, E. C.; Thomasova, D.;
Pasquali, M.; Boycott, K.; Nielan, E. G.; Kartashov, A.; Forman, M.
S.; Tucker, S.; Kimonis, K.; Mumm, S.; Whyte, M. P.; Smith, C. D.;
Watts, G. D. J.: Clinical studies in familial VCP myopathy associated
with Paget disease of bone and frontotemporal dementia. Am. J. Med.
Genet. 146A: 745-757, 2008.
7. Kovach, M. J.; Waggoner, B.; Leal, S. M.; Gelber, D.; Khardori,
R.; Levenstien, M. A.; Shanks, C. A.; Gregg, G.; Al-Lozi, M. T.; Miller,
T.; Rakowica, W.; Lopate, G.; Florence, J.; Glosser, G.; Simmons,
Z.; Morris, J. C.; Whyte, M. P.; Pestronk, A.; Kimonis, V. E.: Clinical
delineation and localization to chromosome 9p13.3-p12 of a unique
dominant disorder in four families: hereditary inclusion body myopathy,
Paget disease of bone, and frontotemporal dementia. Molec. Genet.
Metab. 74: 458-475, 2001.
8. Mackenzie, I. R. A.; Neumann, M.; Bigio, E. H.; Cairns, N. J.;
Alafuzoff, I.; Kril, J.; Kovacs, G. G.; Ghetti, B.; Halliday, G.;
Holm, I. E.; Ince, P. G.; Kamphorst, W.; and 9 others: Nomenclature
and nosology for neuropathologic subtypes of frontotemporal lobar
degeneration: an update. Acta Neuropath. 119: 1-4, 2010.
9. Mehta, S. G.; Khare, M.; Ramani, R.; Watts, G. D. J.; Simon, M.;
Osann, K. E.; Donkervoort, S.; Dec, E.; Nalbandian, A.; Platt, J.;
Pasquali, M.; Wang, A.; Mozaffar, T.; Smith, C. D.; Kimonis, V. E.
: Genotype-phenotype studies of VCP-associated inclusion body myopathy
with Paget disease of bone and/or frontotemporal dementia. Clin.
Genet. 83: 422-431, 2013.
10. Sacconi, S.; Camano, P.; de Greef, J. C.; Lemmers, R. J. L. F.;
Salviati, L.; Boileau, P.; Lopez de Munain Arregui, A.; van der Maarel,
S. M.; Desnuelle, C.: Patients with a phenotype consistent with facioscapulohumeral
muscular dystrophy display genetic and epigenetic heterogeneity. J.
Med. Genet. 49: 41-46, 2012.
11. Schroder, R.; Watts, G. D. J.; Mehta, S. G.; Evert, B. O.; Broich,
P.; Fliessbach, K.; Pauls, K.; Hans, V. H.; Kimonis, V.; Thal, D.
R.: Mutant valosin-containing protein causes a novel type of frontotemporal
dementia. Ann. Neurol. 57: 457-461, 2005.
12. Tucker, W. S., Jr.; Hubbard, W. H.; Stryker, T. D.; Morgan, S.
W.; Evans, O. B.; Freemon, F. R.; Theil, G. B.: A new familial disorder
of combined lower motor neuron degeneration and skeletal disorganization. Trans.
Assoc. Am. Phys. 95: 126-134, 1982.
13. van der Zee, J.; Pirici, D.; Van Langenhove, T.; Engelborghs,
S.; Vandenberghe, R.; Hoffmann, M.; Pusswald, G.; Van den Broeck,
M.; Peeters, K.; Mattheijssens, M.; Martin, J.-J.; De Deyn, P. P.;
Cruts, M.; Haubenberger, D.; Kumar-Singh, S.; Zimprich, A.; Van Broeckhoven,
C.: Clinical heterogeneity in 3 unrelated families linked to VCP
p.Arg159His. Neurology 73: 626-632, 2009.
14. Viassolo, V.; Previtali, S. C.; Schiatti, E.; Magnani, G.; Minetti,
C.; Zara, F.; Grasso, M.; Dagna-Bricarelli, F.; Di Maria, E.: Inclusion
body myopathy, Paget's disease of the bone and frontotemporal dementia:
recurrence of the VCP R155H mutation in an Italian family and implications
for genetic counselling. Clin. Genet. 74: 54-60, 2008.
15. Watts, G. D. J.; Wymer, J.; Kovach, M. J.; Mehta, S. G.; Mumm,
S.; Darvish, D.; Pestronk, A.; Whyte, M. P.; Kimonis, V. E.: Inclusion
body myopathy associated with Paget disease of bone and frontotemporal
dementia is caused by mutant valosin-containing protein. Nature Genet. 36:
377-381, 2004.
16. Weihl, C. C.; Miller, S. E.; Hanson, P. I.; Pestronk, A.: Transgenic
expression of inclusion body myopathy associated mutant p97/VCP causes
weakness and ubiquitinated protein inclusions in mice. Hum. Molec.
Genet. 16: 919-928, 2007.
17. Weihl, C. C.; Pestronk, A.; Kimonis, V. E.: Valosin-containing
protein disease: Inclusion body myopathy with Paget's disease of the
bone and fronto-temporal dementia. Neuromusc. Disord. 19: 308-315,
2009.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Face];
Facial weakness (less common)
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Winged scapulae
SKELETAL:
Paget disease (in 50% of patients);
[Spine];
Back pain;
Lumbar lordosis;
[Pelvis];
Hip pain
MUSCLE, SOFT TISSUE:
Muscle weakness (in 90% of patients);
Proximal muscle weakness;
Shoulder weakness and atrophy;
Limb weakness and atrophy;
Pelvic girdle weakness and atrophy;
Distal muscle atrophy;
Nonspecific myopathic changes seen on biopsy;
Rimmed vacuoles;
Inclusion body myopathy;
Difficulty walking up stairs;
Primary myopathic changes seen on EMG
NEUROLOGIC:
[Central nervous system];
Gait abnormalities;
Frontotemporal dementia (in 30% of patients);
Dystonia;
Expressive dysphasia;
Dystrophic neurites;
Ubiquitin-positive intranuclear neuronal inclusions;
VCP-positive inclusions;
TDP43-positive inclusions;
MRI shows frontal and temporal cortical atrophy
LABORATORY ABNORMALITIES:
Increased serum creatine kinase;
Increased serum bone-specific alkaline phosphatase
MISCELLANEOUS:
Mean age at onset of muscle disease is 42 years (range 24-61);
Mean age at onset of bone disease is 40 years (range 23-65);
Mean age at onset of dementia is 57 years;
Many patients become wheelchair-bound;
Incomplete penetrance of the 3 main clinical signs, myopathy, dementia,
and Paget disease
MOLECULAR BASIS:
Caused by mutation in the valosin-containing protein gene (VCP, 601023.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 4/25/2012
Cassandra L. Kniffin - updated: 3/24/2008
Joanna S. Amberger - updated: 3/10/2005
*FIELD* CD
Cassandra L. Kniffin: 11/12/2002
*FIELD* ED
joanna: 10/22/2013
joanna: 7/2/2013
joanna: 5/8/2012
ckniffin: 4/25/2012
ckniffin: 10/29/2009
ckniffin: 4/23/2009
ckniffin: 8/21/2008
ckniffin: 3/24/2008
ckniffin: 2/5/2007
alopez: 7/28/2005
ckniffin: 5/16/2005
joanna: 3/10/2005
alopez: 4/6/2004
joanna: 11/12/2002
ckniffin: 11/12/2002
*FIELD* CN
Cassandra L. Kniffin - updated: 12/17/2013
Cassandra L. Kniffin - updated: 4/25/2012
Cassandra L. Kniffin - updated: 12/8/2011
George E. Tiller - updated: 12/1/2011
Cassandra L. Kniffin - updated: 3/8/2011
Cassandra L. Kniffin - updated: 12/21/2009
Cassandra L. Kniffin - updated: 10/29/2009
Cassandra L. Kniffin - updated: 4/23/2009
Cassandra L. Kniffin - updated: 3/24/2008
Cassandra L. Kniffin - updated: 2/5/2007
Cassandra L. Kniffin - updated: 5/18/2005
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 12/19/2013
mcolton: 12/18/2013
ckniffin: 12/17/2013
alopez: 10/18/2013
alopez: 9/25/2013
alopez: 9/24/2013
carol: 4/26/2012
ckniffin: 4/25/2012
carol: 12/16/2011
ckniffin: 12/8/2011
alopez: 12/5/2011
terry: 12/1/2011
carol: 9/16/2011
carol: 6/1/2011
wwang: 5/18/2011
ckniffin: 5/5/2011
wwang: 3/11/2011
ckniffin: 3/8/2011
wwang: 1/14/2010
ckniffin: 12/21/2009
terry: 12/1/2009
wwang: 11/5/2009
ckniffin: 10/29/2009
wwang: 5/13/2009
ckniffin: 4/23/2009
wwang: 4/3/2008
ckniffin: 3/24/2008
terry: 1/4/2008
carol: 5/10/2007
wwang: 2/9/2007
ckniffin: 2/5/2007
wwang: 5/27/2005
ckniffin: 5/18/2005
carol: 1/13/2005
mimadm: 1/14/1995
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988
reenie: 6/2/1986
*RECORD*
*FIELD* NO
167320
*FIELD* TI
#167320 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE WITH OR WITHOUT
FRONTOTEMPORAL DEMENTIA 1; IBMPFD1
read more;;MULTISYSTEM PROTEINOPATHY 1; MSP1;;
MUSCULAR DYSTROPHY, LIMB-GIRDLE, WITH PAGET DISEASE OF BONE;;
PAGETOID AMYOTROPHIC LATERAL SCLEROSIS;;
PAGETOID NEUROSKELETAL SYNDROME;;
LOWER MOTOR NEURON DEGENERATION WITH PAGET-LIKE BONE DISEASE
*FIELD* TX
A number sign (#) is used with this entry because inclusion body
myopathy with Paget disease and frontotemporal dementia (IBMPFD1) is
caused by mutation in valosin-containing protein (VCP; 601023).
See also amyotrophic lateral sclerosis-14 with or without frontotemporal
dementia (ALS14; 613954), which is also caused by heterozygous mutation
in the VCP gene and can show overlapping clinical features.
DESCRIPTION
IBMPFD is an autosomal dominant disorder characterized by incomplete
penetrance of 3 main features: disabling muscle weakness (in 90%),
osteolytic bone lesions consistent with Paget disease (in 51%), and
frontotemporal dementia (in 32%).
Weihl et al. (2009) presented a detailed review of the disorder.
Importantly, muscle weakness is an isolated symptom in about 30% of
patients, and is the presenting symptom in greater than half of
patients, suggesting that IBMPFD may be commonly seen in a neuromuscular
clinic without its other syndromic features.
- Genetic Heterogeneity of IBMPFD
IBMPFD2 (615422) is caused by mutation in the HNRNPA2B1 gene (600124) on
chromosome 7p15. IBMPFD3 (615424) is caused by mutation in the HNRNPA1
gene (164017) on chromosome 12q13.
CLINICAL FEATURES
Tucker et al. (1982) studied a large kindred with a syndrome of lower
motor neuron degeneration and polyostotic skeletal disorganization
resembling Paget disease of bone (PDB; 602080). The disorder begins
insidiously at about age 35 with weakness and atrophy of the leg and
proximal arm muscles. Nerve conductions are normal; EMG shows muscle
denervation, as does muscle biopsy. The disorder progresses to
wheelchair confinement and later to bed confinement, quadriparesis,
dementia, respiratory failure, and death before age 60 years. Even early
in the neurologic illness, patients have coarse trabeculation, cortical
thickening, and spotty sclerosis on bone x-rays; diffusely increased
uptake of radionuclide and elevated heat-labile serum alkaline
phosphatase. The disorder affected 6 females and 6 males in 5 sibships
of 3 generations with no instance of male-to-male transmission.
Kimonis et al. (2000) described a family in which autosomal dominant
limb-girdle muscular dystrophy (LGMD) was associated with early-onset
Paget disease of bone PDB and cardiomyopathy. Eight of 11 affected
individuals had both disorders. Onset of PDB occurred at a mean age of
35 years, with classic distribution involving the spine, pelvis, and
skull. Muscle weakness and atrophy was progressive with mildly elevated
to normal CPK levels. Muscle biopsy in the oldest male revealed
vacuolated fibers, but in others revealed nonspecific myopathy. Affected
individuals die from progressive muscle weakness and respiratory and
cardiac failure in their forties to sixties.
Kovach et al. (2001) described the clinical, biochemical, radiologic,
and pathologic characteristics of 49 affected individuals from the
family described by Kimonis et al. (2000) and 3 other unrelated families
with autosomal dominant inclusion body myopathy (IBM), PDB, and
frontotemporal dementia. Ninety percent of the patients had myopathy,
43% had PDB, and 37% had premature frontotemporal dementia.
Watts et al. (2004) reported 13 families with IBMPFD, 12 from the U.S.
and 1 from Canada. Among those individuals, 82% of affected individuals
had myopathy, 49% had PDB, and 30% had early-onset frontotemporal
dementia. The mean age at presentation was 42 years for both IBM and
PDB, whereas frontotemporal dementia typically presented at age 53
years. In IBMPFD myopathic muscle and PDB osteoclasts, inclusions appear
similar, suggestive of disruptions in the same pathologic pathway.
Family 11 in the report by Watts et al. (2004) was originally reported
by Tucker et al. (1982) (Kimonis, 2005).
Haubenberger et al. (2005) reported an Austrian family in which 4 sibs
had autosomal dominant inclusion body myopathy and Paget disease
associated with a heterozygous mutation in the VCP gene (R159H;
601023.0007). None of the affected individuals developed frontotemporal
dementia even though all were over 60 years of age. Haubenberger et al.
(2005) noted that only approximately 30% of patients with VCP mutations
develop dementia, illustrating phenotypic variability. In a follow-up of
this family, van der Zee et al. (2009) noted that 1 patient had
developed dementia at age 64. Van der Zee et al. (2009) also identified
the R159H mutation in affected members of 2 unrelated Belgian families.
In 1 family, patients presented with frontotemporal lobar degeneration
only, whereas in the other family, patients developed frontotemporal
lobar degeneration, Paget disease of the bone, or both without signs of
inclusion body myopathy for any of the mutation carriers. Haplotype
analysis showed that the 2 families and the Austrian family reported by
Haubenberger et al. (2005) were unrelated. Autopsy data of 3 patients
from the 2 Belgian families showed frontotemporal lobar degeneration
with numerous ubiquitin-immunoreactive, intranuclear inclusions and
dystrophic neurites staining positive for TDP43 (TARDBP; 605078)
protein. Van der Zee et al. (2009) commented on the high degree of
clinical heterogeneity and incomplete penetrance of the disorder in
different families carrying the same mutation.
Kimonis et al. (2008) reported detailed clinical features of 49 patients
from 9 families with IBMPFD confirmed by genetic analysis. One family
had been previously reported by Tucker et al. (1982). Forty-two (86%)
patients had muscle disease, the majority of whom were initially
misdiagnosed as having some other form of muscular dystrophy or spinal
muscular atrophy. Weakness was distal and/or proximal, and many patients
were confined to wheelchairs. Muscle biopsies showed inclusion bodies
and/or rimmed vacuoles (39%) or nonspecific changes. Frontotemporal
dementia was diagnosed in 13 (27%) of 49 individuals at a mean age of 57
years, of whom 3 had been originally diagnosed with Alzheimer disease
(104300). Paget disease of bone was found in 28 (57%) of 49 patients at
a mean age of 40 years and correlated with increased serum alkaline
phosphatase. Kimonis et al. (2008) postulated that IBMPFD is
underdiagnosed among patients with myopathy and/or dementia.
Viassolo et al. (2008) reported an Italian family in which 2 sibs and
their mother had IBMPFD. All 3 had progressive inclusion body myopathy
and rapidly progressive severe dementia, but only 1 developed Paget
disease. Genetic analysis identified a heterozygous mutation in the VCP
gene (R155H; 601023.0001). Several other family members were reportedly
affected. Viassolo et al.(2008) discussed the implications of the
incomplete penetrance of some of the features for genetic counseling.
Kim et al. (2011) reported 3 Korean sibs with IBMPFD confirmed by
genetic analysis (601023.0002). The proband developed progressive
dementia presenting as fluent aphasia and language difficulties with
onset at age 47. She never developed myopathy, but did develop
asymptomatic Paget disease with increased serum alkaline phosphatase and
lytic bone lesions on imaging. Her brother developed slowly progressive
proximal muscle weakness at age 50, followed by frontotemporal dementia
characterized initially by comprehension defects at age 54. He never had
Paget disease, although serum alkaline phosphatase was increased. A
second brother developed muscle weakness at age 47, followed by Paget
disease at age 53, and dementia at age 61. Brain MRI in all patients
showed asymmetric atrophy in the anterior inferior and lateral temporal
lobes and inferior parietal lobule with ventricular dilatation on the
affected side (2 on the left, 1 on the right). Two had glucose
hypometabolism in the lateral temporal and inferior parietal areas, with
less involvement of the anterior temporal and frontal lobes compared to
those with typical semantic dementia.
Sacconi et al. (2012) reported 2 unrelated men in their fifties who
presented with a phenotype reminiscent of FSHD1 (158900) but were found
to carry a heterozygous VCP mutation (R191Q; 601023.0006). One had
scapuloperoneal weakness without facial involvement and increased serum
creatine kinase. The second patient had facial weakness, shoulder and
pelvic girdle weakness, and anterior foreleg weakness. Creatine kinase
was increased 4-fold. Muscle biopsies of both patients showed mild
dystrophic changes, but no inclusion bodies. Both had a myopathic
pattern on EMG. One was later found to have a mild dysexecutive
syndrome, but neither had evidence of Paget disease.
- Neuropathologic Findings
Schroder et al. (2005) reported a patient with frontotemporal dementia
(FTD) and inclusion body myopathy caused by mutation in the VCP gene
(601023.0002). There was no evidence of Paget disease. Neuropathologic
examination showed cortical atrophy and widespread neuronal loss;
subcortical neuronal loss was less severe. The cerebral and cerebellar
white matter had severe astrogliosis. Surviving cortical pyramidal
neurons contained VCP- and ubiquitin (see 191321)-positive intranuclear
inclusions and displayed cytoplasmic autofluorescence consistent with
lipofuscin. Nuclear inclusions were not seen in astrocytes,
oligodendrocytes, or microglial cells. Western blot analysis showed a
single 97-kD band corresponding to normal-sized VCP that was similar to
control brains. Schroder et al. (2005) concluded that mutant VCP causes
a novel form of frontotemporal dementia, distinct from tau (MAPT;
157140)-associated FTD (see 600274), characterized by neuronal nuclear
inclusions containing ubiquitin and VCP. The authors suggested that
mutant VCP interferes with ubiquitin-dependent pathways, leading to
abnormal intracellular and intranuclear protein aggregation.
MAPPING
In a family with autosomal dominant LGMD associated with early-onset PDB
and cardiomyopathy, Kimonis et al. (2000) excluded autosomal dominant
and recessive LGMD, PDB, and cardiomyopathy loci. They argued that their
linkage analysis data indicated a unique locus in this family.
By linkage analysis, Kovach et al. (2001) localized autosomal dominant
IBM with PDB and frontotemporal dementia to a 1.08- to 6.46-cM critical
interval on 9p13.3-p12 in the region of autosomal recessive IBM2
(600737). The maximum lod score generated from the combined genotype
data was 9.29 for marker D91791.
MOLECULAR GENETICS
Watts et al. (2004) performed haplotype analysis of 13 families with
IBMPFD and identified 2 ancestral disease-associated haplotypes,
distinguishing families 1, 3, 7, and 16 (group A) from families 2 and 5
(group B). Both groups were of northern European ancestry. The
predominant IBMPFD haplotype of group A includes a core haplotype
flanked by D9S1118 and D9S234, probably transmitted from a shared
ancestor. Watts et al. (2004) identified 6 missense mutations in the
valosin-containing protein (VCP; 601023) in these families. Families 1,
3, 4, 7, 10, 15, and 16 shared the R155H mutation in exon 5
(601023.0001); families 2 and 5 had an R155C mutation (601023.0002); and
family 11 had an R155P mutation (601023.0005). Thus, 10 of the 13
families with IBMPFD had an amino acid change at codon 155 in VCP, which
therefore seems to be a mutation hotspot. In addition, 1 family had a
missense mutation at codon 232 (601023.0003), another at codon 95
(601023.0004), and another at codon 191 (601023.0006).
GENOTYPE/PHENOTYPE CORRELATIONS
Mehta et al. (2013) analyzed clinical and biochemical markers from a
database of 190 individuals from 27 families harboring 10 missense
mutations in the VCP gene. Among these, 145 mutation carriers were
symptomatic and 45 were presymptomatic. The most common clinical feature
(in 91% of patients) was onset of myopathic weakness at a mean age of 43
years. Paget disease of the bone was found in 52% of patients at a mean
age of 41 years. Frontotemporal dementia occurred in 30% of patients at
a mean age of 55 years. Significant genotype-phenotype correlations were
difficult to establish because of small numbers. However, patients with
the R155C mutation had a more severe phenotype with an earlier onset of
myopathy and Paget disease, as well as decreased survival, compared to
those with the R155H mutation. A diagnosis of ALS was found in at least
13 (8.9%) individuals from the 27 families, including 10 patients with
the R155H mutation, and 5 (3%) patients were diagnosed with Parkinson
disease.
NOMENCLATURE
IBMPFD may also be referred to as FTLD-TDP (or TDP43), VCP-related,
based on neuropathologic findings (MacKenzie et al., 2010).
ANIMAL MODEL
Weihl et al. (2007) found that transgenic mice overexpressing the R155H
mutation became progressively weaker in a dose-dependent manner starting
at 6 months of age. There was abnormal muscle pathology, with coarse
internal architecture, vacuolation and disorganized membrane morphology
with reduced caveolin-3 (CAV3; 601253) expression at the sarcolemma.
Even before animals displayed measurable weakness, there was an increase
in ubiquitin-containing protein inclusions and high molecular weight
ubiquitinated proteins. These findings suggested a dysregulation in
protein degradation.
Custer et al. (2010) developed and characterized transgenic mice with
ubiquitous expression of wildtype and disease-causing versions of human
VCP/p97. Mice expressing VCP/p97 harboring the mutations R155H
(601023.0001) or A232E (601023.0003) exhibited progressive muscle
weakness, and developed inclusion body myopathy including rimmed
vacuoles and TDP43 pathology. The brain showed widespread TDP43 (605078)
pathology, and the skeleton exhibited severe osteopenia accompanied by
focal lytic and sclerotic lesions in vertebrae and femur. In vitro
studies indicated that mutant VCP caused inappropriate activation of the
NF-kappa-B (see 164011) signaling cascade, which could contribute to the
mechanism of pathogenesis in multiple tissues including muscle, bone,
and brain.
*FIELD* RF
1. Custer, S. K.; Neumann, M.; Lu, H.; Wright, A. C.; Taylor, J. P.
: Transgenic mice expressing mutant forms VCP/p97 recapitulate the
full spectrum of IBMPFD including degeneration in muscle, brain and
bone. Hum. Molec. Genet. 19: 1741-1755, 2010.
2. Haubenberger, D.; Bittner, R. E.; Rauch-Shorny, S.; Zimprich, F.;
Mannhalter, C.; Wagner, L.; Mineva, I.; Vass, K.; Auff, E.; Zimprich,
A.: Inclusion body myopathy and Paget disease is linked to a novel
mutation in the VCP gene. Neurology 65: 1304-1305, 2005.
3. Kim, E.-J.; Park, Y.-E.; Kim, D.-S.; Ahn, B.-Y.; Kim, H.-S.; Chang,
Y. H.; Kim, S.-J,; Kim, H.-J.; Lee, H.-W.; Seeley, W. W.; Kim, S.
: Inclusion body myopathy with Paget disease of bone and frontotemporal
dementia linked to VCP p.Arg155Cys in a Korean family. Arch. Neurol. 68:
787-796, 2011.
4. Kimonis, V. E.: Personal Communication. Boston, Mass. 1/12/2005.
5. Kimonis, V. E.; Kovach, M. J.; Waggoner, B.; Leal, S.; Salam, A.;
Rimer, L.; Davis, K.; Khardori, R.; Gelber, D.: Clinical and molecular
studies in a unique family with autosomal dominant limb-girdle muscular
dystrophy and Paget disease of bone. Genet. Med. 2: 232-241, 2000.
6. Kimonis, V. E.; Mehta, S. G.; Fulchiero, E. C.; Thomasova, D.;
Pasquali, M.; Boycott, K.; Nielan, E. G.; Kartashov, A.; Forman, M.
S.; Tucker, S.; Kimonis, K.; Mumm, S.; Whyte, M. P.; Smith, C. D.;
Watts, G. D. J.: Clinical studies in familial VCP myopathy associated
with Paget disease of bone and frontotemporal dementia. Am. J. Med.
Genet. 146A: 745-757, 2008.
7. Kovach, M. J.; Waggoner, B.; Leal, S. M.; Gelber, D.; Khardori,
R.; Levenstien, M. A.; Shanks, C. A.; Gregg, G.; Al-Lozi, M. T.; Miller,
T.; Rakowica, W.; Lopate, G.; Florence, J.; Glosser, G.; Simmons,
Z.; Morris, J. C.; Whyte, M. P.; Pestronk, A.; Kimonis, V. E.: Clinical
delineation and localization to chromosome 9p13.3-p12 of a unique
dominant disorder in four families: hereditary inclusion body myopathy,
Paget disease of bone, and frontotemporal dementia. Molec. Genet.
Metab. 74: 458-475, 2001.
8. Mackenzie, I. R. A.; Neumann, M.; Bigio, E. H.; Cairns, N. J.;
Alafuzoff, I.; Kril, J.; Kovacs, G. G.; Ghetti, B.; Halliday, G.;
Holm, I. E.; Ince, P. G.; Kamphorst, W.; and 9 others: Nomenclature
and nosology for neuropathologic subtypes of frontotemporal lobar
degeneration: an update. Acta Neuropath. 119: 1-4, 2010.
9. Mehta, S. G.; Khare, M.; Ramani, R.; Watts, G. D. J.; Simon, M.;
Osann, K. E.; Donkervoort, S.; Dec, E.; Nalbandian, A.; Platt, J.;
Pasquali, M.; Wang, A.; Mozaffar, T.; Smith, C. D.; Kimonis, V. E.
: Genotype-phenotype studies of VCP-associated inclusion body myopathy
with Paget disease of bone and/or frontotemporal dementia. Clin.
Genet. 83: 422-431, 2013.
10. Sacconi, S.; Camano, P.; de Greef, J. C.; Lemmers, R. J. L. F.;
Salviati, L.; Boileau, P.; Lopez de Munain Arregui, A.; van der Maarel,
S. M.; Desnuelle, C.: Patients with a phenotype consistent with facioscapulohumeral
muscular dystrophy display genetic and epigenetic heterogeneity. J.
Med. Genet. 49: 41-46, 2012.
11. Schroder, R.; Watts, G. D. J.; Mehta, S. G.; Evert, B. O.; Broich,
P.; Fliessbach, K.; Pauls, K.; Hans, V. H.; Kimonis, V.; Thal, D.
R.: Mutant valosin-containing protein causes a novel type of frontotemporal
dementia. Ann. Neurol. 57: 457-461, 2005.
12. Tucker, W. S., Jr.; Hubbard, W. H.; Stryker, T. D.; Morgan, S.
W.; Evans, O. B.; Freemon, F. R.; Theil, G. B.: A new familial disorder
of combined lower motor neuron degeneration and skeletal disorganization. Trans.
Assoc. Am. Phys. 95: 126-134, 1982.
13. van der Zee, J.; Pirici, D.; Van Langenhove, T.; Engelborghs,
S.; Vandenberghe, R.; Hoffmann, M.; Pusswald, G.; Van den Broeck,
M.; Peeters, K.; Mattheijssens, M.; Martin, J.-J.; De Deyn, P. P.;
Cruts, M.; Haubenberger, D.; Kumar-Singh, S.; Zimprich, A.; Van Broeckhoven,
C.: Clinical heterogeneity in 3 unrelated families linked to VCP
p.Arg159His. Neurology 73: 626-632, 2009.
14. Viassolo, V.; Previtali, S. C.; Schiatti, E.; Magnani, G.; Minetti,
C.; Zara, F.; Grasso, M.; Dagna-Bricarelli, F.; Di Maria, E.: Inclusion
body myopathy, Paget's disease of the bone and frontotemporal dementia:
recurrence of the VCP R155H mutation in an Italian family and implications
for genetic counselling. Clin. Genet. 74: 54-60, 2008.
15. Watts, G. D. J.; Wymer, J.; Kovach, M. J.; Mehta, S. G.; Mumm,
S.; Darvish, D.; Pestronk, A.; Whyte, M. P.; Kimonis, V. E.: Inclusion
body myopathy associated with Paget disease of bone and frontotemporal
dementia is caused by mutant valosin-containing protein. Nature Genet. 36:
377-381, 2004.
16. Weihl, C. C.; Miller, S. E.; Hanson, P. I.; Pestronk, A.: Transgenic
expression of inclusion body myopathy associated mutant p97/VCP causes
weakness and ubiquitinated protein inclusions in mice. Hum. Molec.
Genet. 16: 919-928, 2007.
17. Weihl, C. C.; Pestronk, A.; Kimonis, V. E.: Valosin-containing
protein disease: Inclusion body myopathy with Paget's disease of the
bone and fronto-temporal dementia. Neuromusc. Disord. 19: 308-315,
2009.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Face];
Facial weakness (less common)
CHEST:
[Ribs, sternum, clavicles, and scapulae];
Winged scapulae
SKELETAL:
Paget disease (in 50% of patients);
[Spine];
Back pain;
Lumbar lordosis;
[Pelvis];
Hip pain
MUSCLE, SOFT TISSUE:
Muscle weakness (in 90% of patients);
Proximal muscle weakness;
Shoulder weakness and atrophy;
Limb weakness and atrophy;
Pelvic girdle weakness and atrophy;
Distal muscle atrophy;
Nonspecific myopathic changes seen on biopsy;
Rimmed vacuoles;
Inclusion body myopathy;
Difficulty walking up stairs;
Primary myopathic changes seen on EMG
NEUROLOGIC:
[Central nervous system];
Gait abnormalities;
Frontotemporal dementia (in 30% of patients);
Dystonia;
Expressive dysphasia;
Dystrophic neurites;
Ubiquitin-positive intranuclear neuronal inclusions;
VCP-positive inclusions;
TDP43-positive inclusions;
MRI shows frontal and temporal cortical atrophy
LABORATORY ABNORMALITIES:
Increased serum creatine kinase;
Increased serum bone-specific alkaline phosphatase
MISCELLANEOUS:
Mean age at onset of muscle disease is 42 years (range 24-61);
Mean age at onset of bone disease is 40 years (range 23-65);
Mean age at onset of dementia is 57 years;
Many patients become wheelchair-bound;
Incomplete penetrance of the 3 main clinical signs, myopathy, dementia,
and Paget disease
MOLECULAR BASIS:
Caused by mutation in the valosin-containing protein gene (VCP, 601023.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 4/25/2012
Cassandra L. Kniffin - updated: 3/24/2008
Joanna S. Amberger - updated: 3/10/2005
*FIELD* CD
Cassandra L. Kniffin: 11/12/2002
*FIELD* ED
joanna: 10/22/2013
joanna: 7/2/2013
joanna: 5/8/2012
ckniffin: 4/25/2012
ckniffin: 10/29/2009
ckniffin: 4/23/2009
ckniffin: 8/21/2008
ckniffin: 3/24/2008
ckniffin: 2/5/2007
alopez: 7/28/2005
ckniffin: 5/16/2005
joanna: 3/10/2005
alopez: 4/6/2004
joanna: 11/12/2002
ckniffin: 11/12/2002
*FIELD* CN
Cassandra L. Kniffin - updated: 12/17/2013
Cassandra L. Kniffin - updated: 4/25/2012
Cassandra L. Kniffin - updated: 12/8/2011
George E. Tiller - updated: 12/1/2011
Cassandra L. Kniffin - updated: 3/8/2011
Cassandra L. Kniffin - updated: 12/21/2009
Cassandra L. Kniffin - updated: 10/29/2009
Cassandra L. Kniffin - updated: 4/23/2009
Cassandra L. Kniffin - updated: 3/24/2008
Cassandra L. Kniffin - updated: 2/5/2007
Cassandra L. Kniffin - updated: 5/18/2005
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 12/19/2013
mcolton: 12/18/2013
ckniffin: 12/17/2013
alopez: 10/18/2013
alopez: 9/25/2013
alopez: 9/24/2013
carol: 4/26/2012
ckniffin: 4/25/2012
carol: 12/16/2011
ckniffin: 12/8/2011
alopez: 12/5/2011
terry: 12/1/2011
carol: 9/16/2011
carol: 6/1/2011
wwang: 5/18/2011
ckniffin: 5/5/2011
wwang: 3/11/2011
ckniffin: 3/8/2011
wwang: 1/14/2010
ckniffin: 12/21/2009
terry: 12/1/2009
wwang: 11/5/2009
ckniffin: 10/29/2009
wwang: 5/13/2009
ckniffin: 4/23/2009
wwang: 4/3/2008
ckniffin: 3/24/2008
terry: 1/4/2008
carol: 5/10/2007
wwang: 2/9/2007
ckniffin: 2/5/2007
wwang: 5/27/2005
ckniffin: 5/18/2005
carol: 1/13/2005
mimadm: 1/14/1995
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988
reenie: 6/2/1986
MIM
601023
*RECORD*
*FIELD* NO
601023
*FIELD* TI
*601023 VALOSIN-CONTAINING PROTEIN; VCP
;;CDC48, YEAST, HOMOLOG OF;;
p97
*FIELD* TX
read more
DESCRIPTION
The VCP gene encodes valosin-containing protein, a ubiquitously
expressed multifunctional protein that is a member of the AAA+ (ATPase
associated with various activities) protein family. It has been
implicated in multiple cellular functions ranging from organelle
biogenesis to ubiquitin-dependent protein degradation (summary by Weihl
et al., 2009).
CLONING
Clathrin is a structural protein found in coated pits and vesicles,
organelles which are important in membrane trafficking functions such as
endocytosis and Golgi sorting. A 100-kD protein, designated
valosin-containing protein or VCP by early investigators, is a
structural protein complexed with clathrin (see 118960). VCP is the
homolog of yeast cdc48p, and is a member of a family that includes
putative ATP-binding proteins involved in vesicle transport and fusion,
26S proteasome function, and assembly of peroxisomes (Pleasure et al.,
1993). VCP was cloned from the pig (Koller and Brownstein, 1987) and
mouse (Egerton et al., 1992). Druck et al. (1995) cloned a portion of
the human cDNA.
Cloutier et al. (2013) stated that the deduced 806-amino acid VCP
protein contains an N-terminal domain, followed by a linker region, an
ATPase domain, a second linker region, a second ATPase domain, and a
C-terminal domain. The N-terminal domain consists of a double-psi-barrel
superfold and 4-stranded beta barrel, and each ATPase domain consists of
Walker A and B motifs and a 4-alpha-helix bundle. VCP is extensively
modified by phosphorylation and acetylation, as well as by lysine
methylation.
GENE STRUCTURE
Johnson et al. (2010) noted that the VCP gene contains 17 exons.
MAPPING
Druck et al. (1995) used a partial human VCP cDNA to probe a panel of
somatic cell hybrid DNAs and mapped the VCP gene to chromosome
9pter-q34.
By database analysis, Hoyle et al. (1997) identified a human expressed
sequence tag (EST) that shares 80% identity with the mouse 3-prime
untranslated region. They designed primers to this EST and amplified and
sequenced a 127-bp product from total human DNA. This product detected 1
fragment only in a HindIII digest of total human DNA, indicating there
is only 1 VCP sequence in the human genome. Using the 127-bp sequence to
screen a human PAC library, followed by FISH analysis, they mapped the
VCP gene to chromosome 9p13-p12. They mapped the mouse Vcp gene to mouse
chromosome 4 and found a probable pseudogene on the mouse X chromosome.
The VCP gene maps to chromosome 9p13.3 (Johnson et al., 2010).
GENE FUNCTION
Ye et al. (2001) demonstrated that VCP (CDC48 in yeast and p97 in
mammals) is required for the export of endoplasmic reticulum (ER) into
the cytosol. Whereas CDC48/p97 was known to function in a complex with
the cofactor p47 in membrane fusion, Ye et al. (2001) demonstrated that
its role in ER protein export requires the interacting partners UFD1
(601754) and NPL4 (606590). The AAA ATPase interacts with substrates at
the ER membrane and is needed to release them as polyubiquitinated
species into the cytosol.
Zhang et al. (1999) created a substrate-trapping mutant of PTPH1
(176877) that interacted primarily with VCP in vitro but not in cells. A
double mutant of PTPH1 had a marked reduction in phosphotyrosine
content, specifically trapped VCP in vivo, and recognized the C-terminal
tyrosines of VCP. Immunoblot analysis showed that wildtype PTPH1
specifically dephosphorylated VCP. Zhang et al. (1999) concluded that
PTPH1 exerts its effects on cell growth through dephosphorylation of VCP
and that tyrosine phosphorylation is an important regulator of VCP
function.
Watts et al. (2004) summarized that VCP has been associated with several
essential cell protein pathways including cell cycle, homotypic membrane
fusion, nuclear envelope reconstruction, postmitotic Golgi reassembly,
DNA damage response, suppressor of apoptosis, and ubiquitin-dependent
protein degradation. Higashiyama et al. (2002) identified a fruit fly
VCP loss-of-function mutant as a dominant suppressor of expanded
polyglutamine-induced neuronal degeneration. The suppressive effects of
the loss-of-function mutant did not seem to result from inhibition of
polyglutamine aggregate formation but rather from the degree of loss of
VCP function. This suggested that a gene dosage response for VCP
expression is essential to its function in expanded
polyglutamine-induced neuronal degeneration. In support of this idea,
transgenic fruit flies in which VCP levels were elevated experienced
severe apoptotic cell death, whereas homozygous VCP loss-of-function
mutants were embryonic lethal.
Ye et al. (2004) found that VIMP (607918) recruits the p97 ATPase (VCP)
and its cofactor, the UFD1/NPL4 complex, to the ER for
retrotranslocation of misfolded proteins into the cytosol. They noted
that all pathways of retrotranslocation appear to require the function
of the p97 ATPase complex, which may provide the general driving force
for the movement of proteins into the cytosol.
Using a library of endoribonuclease-prepared short interfering RNAs
(esiRNAs), Kittler et al. (2004) identified 37 genes required for cell
division, one of which was VCP. These 37 genes included several splicing
factors for which knockdown generates mitotic spindle defects. In
addition, a putative nuclear-export terminator was found to speed up
cell proliferation and mitotic progression after knockdown.
Uchiyama et al. (2006) found that rodent p37 (610686) formed a complex
with p97 in cytosol and localized to Golgi and ER. Small interfering RNA
experiments in HeLa cells revealed that p37 was required for Golgi and
ER biogenesis. Injection of anti-p37 antibodies into HeLa cells at
different stages of the cell cycle showed that p37 was involved in Golgi
and ER maintenance during interphase and in their reassembly at the end
of mitosis. In an in vitro Golgi reassembly assay, the p97/p37 complex
showed membrane fusion activity that required p115 (603344)-GM130
(GOLGA2; 602580) tethering and SNARE GS15 (BET1L; 615417). VCIP135
(VCPIP1) was also required, but its deubiquitinating activity was
unnecessary for p97/p37-mediated activities.
Ramadan et al. (2007) showed that p97 stimulates nucleus reformation by
inactivating the chromatin-associated kinase Aurora B (604970). During
mitosis, Aurora B inhibits nucleus reformation by preventing chromosome
decondensation and formation of the nuclear envelope membrane. During
exit from mitosis, p97 binds to Aurora B after its ubiquitylation and
extracts it from chromatin. This leads to inactivation of Aurora B on
chromatin, thus allowing chromatin decondensation and nuclear envelope
formation. Ramadan et al. (2007) concluded that their data revealed an
essential pathway that regulates reformation of the nucleus after
mitosis and defined ubiquitin-dependent protein extraction as a common
mechanism of Cdc48/p97 activity also during nucleus formation.
Using human cell lines, Mueller et al. (2008) identified several
components of a protein complex required for retrotranslocation or
dislocation of misfolded proteins from the ER lumen to the cytosol for
proteasome-dependent degradation. These included SEL1L (602329), HRD1
(SYVN1; 608046), derlin-2 (DERL2; 610304), the ATPase p97, PDI (P4HB;
176790), BIP (HSPA5; 138120), calnexin (CANX; 114217), AUP1 (602434),
UBXD8 (FAF2), UBC6E (UBE2J1), and OS9 (609677).
By affinity purification, SDS-PAGE, and mass spectrometry, Cloutier et
al. (2013) found that METTL21D (615260) expressed in HEK293 cells
interacted with endogenous VCP, ASPSCR1 (606236), and UBXN6 (611946). In
vitro methylation assays showed that recombinant METTL21D methylated
VCP, which was abrogated by mutation of lys315 in ATPase domain 1 of
VCP. Methylation reduced the activity of VCP ATPase domain 1, but it had
no effect on the activity of VCP ATPase domain 2. METTL21D did not
methylate ASPSRC1 or UBXN6, but the presence of ASPSRC1, but not UBXN6,
enhanced METTL21D-dependent VCP methylation.
In immunoprecipitation studies, Clemen et al. (2010) identified
strumpellin (KIAA0196; 601657) as a binding partner with VCP.
Strumpellin was detected in pathologic protein aggregates in muscle
tissue derived from patients with IBMPFD1 (167320) as well as in various
myofibrillar myopathies and in cortical neurons of a mouse model of
Huntington disease (HD; 143100). These findings suggested that
strumpellin, like VCP, may have a role in various protein aggregate
diseases.
MOLECULAR GENETICS
- Inclusion Body Myopathy With Paget Disease of Bone and Frontotemporal
Dementia
Watts et al. (2004) identified missense mutations in VCP as the cause of
inclusion body myopathy with Paget disease of bone and frontotemporal
dementia (IBMPFD; 167320). Ten of 13 families with this disorder had an
amino acid change at arginine-155, either to histidine, proline, or
cysteine. Arginine-155 of VCP was conserved in homologs through all
species examined except in 2 C. elegans homologs, which had glutamine at
that position. Arginine-191 was invariant in all species examined, and
arginine-95 was substituted by histidine in only 2 species.
Watts et al. (2004) suggested that since patients with IBMPFD are viable
with relatively late onset of disease, the mutations identified do not
disrupt the cell cycle or apoptosis pathways. They proposed that
mutations in VCP cause Paget disease of bone by compromising ubiquitin
binding and target similar cellular pathways or proteins. They suggested
that the progressive neuronal degeneration has to do with protein
quality control and ubiquitin protein degradation pathways. Finally,
Watts et al. (2004) concluded that because IBMPFD is a dominant
progressive syndrome, the mutations they identified are probably
relatively subtle and aging, oxidative stress, and endoplasmic reticulum
stress probably define a threshold at which the IBMPFD phenotype becomes
manifest.
In vitro functional expression studies by Weihl et al. (2006) showed
that cells transfected with the mutant R155H (601023.0001) and R95G
(601023.0004) proteins developed a prominent increase in diffuse and
aggregated ubiquitin conjugates and showed impaired function of
endoplasmic reticulum-associated degradation (ERAD), as well as a
distorted ER structure.
In human cells with IBMPFD-associated mutations, Ju et al. (2008) found
that treatment with a proteasome inhibitor resulted in increased cell
death and an increase in perinuclear ubiquitinated proteins, but no
clear aggresomes, compared to wildtype. Expression of an aggregate
protein in mutant cells did not result in proper formation of inclusion
bodies or aggresomes. A similar lack of inclusion body formation was
observed in mutant mouse muscle fibers in vivo. Further studies showed
that mutant VCP trapped aggregated proteins but failed to release them
to aggresomes or inclusion bodies. This was reversed upon coexpression
with HDAC6 (300272), a VCP-binding protein that facilitates formation of
aggresomes. Ju et al. (2008) concluded that mutations in the VCP gene
impaired the proper clearance of aggregated proteins.
- Amyotrophic Lateral Sclerosis 14, With or Without Frontotemporal
Dementia
Using exome sequencing, Johnson et al. (2010) identified a heterozygous
mutation in the VCP gene (R191Q; 601023.0006) in 4 affected members of
an Italian family with amyotrophic lateral sclerosis-14 (ALS14; 613954)
with or without frontotemporal dementia. Screening of the VCP gene in
210 familial ALS cases and 78 autopsy-proven ALS cases identified 3
additional pathogenic VCP mutations (601023.0001; 601012.0008, and
601023.0009) in 4 patients. The findings expanded the phenotype
associated with VCP mutations to include classic ALS.
- Functional Effects of VCP Mutations
Cloutier et al. (2013) found that the R155H (601023.0001), R159G
(601023.0007), and R191Q (601023.0006) mutations in VCP did not alter in
vitro methylation of VCP by METTL21D. However, ASPSRC1 did not enhance
methylation of VCP containing these mutations, as it did with wildtype
VCP.
GENOTYPE/PHENOTYPE CORRELATIONS
Mehta et al. (2013) analyzed clinical and biochemical markers from a
database of 190 individuals from 27 families harboring 10 missense
mutations in the VCP gene. Among these, 145 mutation carriers were
symptomatic and 45 were presymptomatic. The most common clinical feature
(in 91% of patients) was onset of myopathic weakness at a mean age of 43
years. Paget disease of the bone was found in 52% of patients at a mean
age of 41 years. Frontotemporal dementia occurred in 30% of patients at
a mean age of 55 years. Significant genotype-phenotype correlations were
difficult to establish because of small numbers. However, patients with
the R155C mutation (60123.0002) had a more severe phenotype with an
earlier onset of myopathy and Paget disease, as well as decreased
survival, compared to those with the R155H mutation (601023.0001). A
diagnosis of ALS was found in at least 13 (8.9%) individuals from the 27
families, including 10 patients with the R155H mutation, and 5 (3%)
patients were diagnosed with Parkinson disease.
ANIMAL MODEL
Weihl et al. (2007) found that transgenic mice overexpressing the R155H
mutation became progressively weaker in a dose-dependent manner starting
at 6 months of age. There was abnormal muscle pathology, with coarse
internal architecture, vacuolation, and disorganized membrane morphology
with reduced caveolin-3 (CAV3; 601253) expression at the sarcolemma.
Even before animals displayed measurable weakness, there was an increase
in ubiquitin-containing protein inclusions and high molecular weight
ubiquitinated proteins. These findings suggested a dysregulation in
protein degradation.
Custer et al. (2010) developed and characterized transgenic mice with
ubiquitous expression of wildtype and disease-causing versions of human
VCP/p97. Mice expressing VCP/p97 harboring the mutations R155H
(601023.0001) or A232E (601023.0003) exhibited progressive muscle
weakness, and developed inclusion body myopathy including rimmed
vacuoles and TDP43 (605078) pathology. The brain showed widespread TDP43
pathology, and the skeleton exhibited severe osteopenia accompanied by
focal lytic and sclerotic lesions in vertebrae and femur. In vitro
studies indicated that mutant VCP caused inappropriate activation of the
NF-kappa-B (see 164011) signaling cascade, which could contribute to the
mechanism of pathogenesis in multiple tissues including muscle, bone,
and brain.
*FIELD* AV
.0001
INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL
DEMENTIA
AMYOTROPHIC LATERAL SCLEROSIS 14 WITHOUT FRONTOTEMPORAL DEMENTIA,
INCLUDED
VCP, ARG155HIS
In 7 of 13 families with autosomal dominant IBMPFD (167320), Watts et
al. (2004) identified a G-to-A transition at nucleotide 464 of the VCP
gene, resulting in an arg155-to-his substitution (R155H). This mutation
appears to have arisen independently on several haplotype backgrounds.
Viassolo et al. (2008) identified heterozygosity for the R155H mutation
in 3 affected members of an Italian family with IBMPFD. All 3 had
progressive inclusion body myopathy and rapidly progressive severe
dementia, but only 1 developed Paget disease.
In vitro functional expression studies by Weihl et al. (2006) showed
that R155H-mutant protein properly assembled into a hexameric structure
and showed normal ATPase activity. Cell transfected with the mutant
protein showed a prominent increase in diffuse and aggregated ubiquitin
conjugates and impaired function of endoplasmic reticulum-associated
degradation (ERAD), as well as a distorted ER structure.
Johnson et al. (2010) identified heterozygosity for the R155H mutation,
which they stated resulted from an 853G-A transition in exon 5, in a
member of the family reported by Watts et al. (2004). However, the
family member reported by Johnson et al. (2010) had classic ALS (ALS14;
613954) without evidence of Paget disease, myopathy, or frontotemporal
dementia. Postmortem examination of this patient showed loss of
brainstem and spinal cord motor neurons with Bunina bodies in surviving
neurons, TDP43 (TARDBP; 605078)-positive immunostaining, and mild pallor
of the lateral descending corticospinal tracts, all features consistent
with diagnosis of ALS. The findings expanded the phenotype associated
with VCP mutations, even within a single family.
.0002
INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL
DEMENTIA
VCP, ARG155CYS
In 2 of 13 families with autosomal dominant IBMPFD (167320), Watts et
al. (2004) identified a C-to-T transition at nucleotide 463 of the VCP
gene, resulting in an arg155-to-cys substitution (R155C).
Kim et al. (2011) identified a heterozygous R155C mutation in 3 Korean
sibs with IBMPFD. The proband developed progressive dementia presenting
as fluent aphasia and language difficulties with onset at age 47. She
never developed myopathy, but did develop asymptomatic Paget disease
with increased serum alkaline phosphatase and lytic bone lesions on
imaging. Her brother developed slowly progressive proximal muscle
weakness at age 50, followed by frontotemporal dementia characterized
initially by comprehension defects at age 54. He never had Paget
disease, although serum alkaline phosphatase was increased. A second
brother developed muscle weakness at age 47, followed by Paget disease
at age 53, and dementia at age 61. Brain MRI in all patients showed
asymmetric atrophy in the anterior inferior and lateral temporal lobes
and inferior parietal lobule with ventricular dilatation on the affected
side (2 on the left, 1 on the right). Two had glucose hypometabolism in
the lateral temporal and inferior parietal areas, with less involvement
of the anterior temporal and frontal lobes compared to those with
typical semantic dementia.
.0003
INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL
DEMENTIA
VCP, ALA232GLU
In 1 of 13 families with autosomal dominant IBMPFD (167320), Watts et
al. (2004) identified a C-to-A transversion at nucleotide 695 of the VCP
gene, resulting in an ala-to-glu change at codon 232 (A232E).
.0004
INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL
DEMENTIA
VCP, ARG95GLY
In 1 of 13 families with autosomal dominant IBMPFD (167320), Watts et
al. (2004) identified a C-to-G transversion at nucleotide 283 of the VCP
gene, resulting in an arg-to-gly substitution at codon 95 (R95G).
In vitro functional expression studies by Weihl et al. (2006) showed
that cells transfected with R95G-mutant protein developed a prominent
increased in diffuse and aggregated ubiquitin conjugates and impaired
function of endoplasmic reticulum-associated degradation (ERAD), as well
as a distorted ER structure.
.0005
INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL
DEMENTIA
VCP, ARG155PRO
In 1 of 13 families with autosomal dominant IBMPFD (167320), Watts et
al. (2004) identified a G-to-C transversion at nucleotide 464 of the VCP
gene, resulting in an arg-to-pro substitution at codon 155 (R155P). This
family was originally reported by Tucker et al. (1982).
.0006
INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL
DEMENTIA
AMYOTROPHIC LATERAL SCLEROSIS 14 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA,
INCLUDED
VCP, ARG191GLN
In 1 of 13 families with autosomal dominant IBMPFD (167320), Watts et
al. (2004) identified a G-to-C transversion at nucleotide 572 of the VCP
gene, resulting in an arg-to-gln substitution at codon 191 (R191Q).
Using exome sequencing, Johnson et al. (2010) identified heterozygosity
for the R191Q mutation in the VCP gene, which they stated resulted from
a 961G-A transition in exon 5, in 4 affected members of an Italian
family with amyotrophic lateral sclerosis-14 (ALS14; 613954). Affected
individuals presented in adulthood with limb-onset motor neuron symptoms
that rapidly progressed to involve all 4 limbs and the bulbar
musculature, consistent with a classical ALS phenotype. All patients had
unequivocal upper and lower motor signs, and none had evidence of Paget
disease. One patient showed mild frontotemporal dementia. Autopsy
material was not available. A parent of the proband had died at age 58
with dementia, parkinsonism, Paget disease, and upper limb weakness,
suggesting IBMPFD. The findings indicated an expanded phenotypic
spectrum for VCP mutations.
Sacconi et al. (2012) identified a heterozygous R191Q mutation in 2
unrelated men in their fifties who presented with a phenotype
reminiscent of FSHD1 (158900). One had scapuloperoneal weakness without
facial involvement and increased serum creatine kinase. The second
patient had facial weakness, shoulder and pelvic girdle weakness, and
anterior foreleg weakness. Creatine kinase was increased 4-fold. Muscle
biopsies of both patients showed mild dystrophic changes, but no
inclusion bodies. EMG showed myopathic patterns. One patient was later
found to have a mild dysexecutive syndrome, but neither had evidence of
Paget disease.
.0007
INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL
DEMENTIA
VCP, ARG159HIS
In 4 affected sibs of an Austrian family with autosomal dominant
inclusion body myopathy and Paget disease but without dementia (167320),
Haubenberger et al. (2005) identified a heterozygous 688G-A transition
in exon 5 of the VCP gene, resulting in an arg159-to-his (R159H)
substitution. The mutation occurred in a highly conserved region close
to the codon 155 hotspot described by Watts et al. (2004) and was not
present in 384 control chromosomes. None of the 4 affected sibs
demonstrated frontotemporal dementia even though all were over 60 years
of age. Haubenberger et al. (2005) noted that only approximately 30% of
patients with VCP mutations develop dementia, illustrating phenotypic
variability. In a follow-up of this family, van der Zee et al. (2009)
noted that 1 patient had developed dementia at age 64. Van der Zee et
al. (2009) also identified the R159H mutation in affected members of 2
unrelated Belgian families. In 1 family, patients presented with
frontotemporal lobar degeneration only, whereas in the other family,
patients developed frontotemporal lobar degeneration, Paget disease of
the bone, or both without signs of inclusion body myopathy for any of
the mutation carriers. Haplotype analysis showed that the 2 families and
the Austrian family reported by Haubenberger et al. (2005) were
unrelated. Autopsy data of 3 patients from the 2 Belgian families showed
frontotemporal lobar degeneration with numerous
ubiquitin-immunoreactive, intranuclear inclusions and dystrophic
neurites staining positive for TDP43 (TARDBP; 605078) protein. Van der
Zee et al. (2009) commented on the high degree of clinical heterogeneity
and incomplete penetrance of the disorder in different families carrying
the same mutation.
.0008
AMYOTROPHIC LATERAL SCLEROSIS 14 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
VCP, ARG159GLY
In affected members of a family with ALS14 with or without
frontotemporal dementia (613954), Johnson et al. (2010) identified a
heterozygous 864C-G transversion in exon 5 of the VCP gene, resulting in
an arg159-to-gly (R159G) substitution in a conserved residue. The
mutation was not found in 3,138 control chromosomes, and a different
pathogenic mutation had previously been reported in this codon (R159H;
601023.0007). Two patients had classic ALS with frontotemporal dementia,
and a third obligate mutation carrier had Paget disease, followed by ALS
without cognitive impairment.
.0009
AMYOTROPHIC LATERAL SCLEROSIS 14 WITHOUT FRONTOTEMPORAL DEMENTIA
VCP, ASP592ASN
In a patient with ALS14 without frontotemporal dementia (613954),
Johnson et al. (2010) identified a heterozygous 2163G-A transition in
exon 14 of the VCP gene, resulting in an asp592-to-asn (D592N)
substitution in a residue directly adjacent to the central pore formed
by the VCP hexamer. The mutation was not found in 3,138 control
chromosomes. A maternal uncle had previously been diagnosed with ALS.
*FIELD* RF
1. Clemen, C. S.; Tangavelou, K.; Strucksberg, K.-H.; Just, S.; Gaertner,
L.; Regus-Leidig, H.; Stumpf, M.; Reimann, J.; Coras, R.; Morgan,
R. O.; Fernandez, M.-P.; Hofmann, A.; Muller, S.; Schoser, B.; Hanisch,
F.-G.; Rottbauer, W.; Blumcke, I.; von Horsten, S.; Eichinger, L.;
Schroder, R.: Strumpellin is a novel valosin-containing protein binding
partner linking hereditary spastic paraplegia to protein aggregation
diseases. Brain 133: 2920-2941, 2010.
2. Cloutier, P.; Lavallee-Adam, M.; Faubert, D.; Blanchette, M.; Coulombe,
B.: A newly uncovered group of distantly related lysine methyltransferases
preferentially interact with molecular chaperones to regulate their
activity. PLoS Genet. 9: e1003210, 2013. Note: Electronic Article.
3. Custer, S. K.; Neumann, M.; Lu, H.; Wright, A. C.; Taylor, J. P.
: Transgenic mice expressing mutant forms VCP/p97 recapitulate the
full spectrum of IBMPFD including degeneration in muscle, brain and
bone. Hum. Molec. Genet. 19: 1741-1755, 2010.
4. Druck, T.; Gu, Y.; Prabhala. G.; Cannizzaro, L. A.; Park, S.-H.;
Huebner, K.; Keen, J. H.: Chromosome localization of human genes
for clathrin adaptor polypeptides AP2-beta and AP50 and the clathrin-binding
protein, VCP. Genomics 30: 94-97, 1995.
5. Egerton, M.; Ashe, O. R.; Chen, D.; Druker, B. J.; Burgess, W.
H.; Samelson, L. E.: VCP, the mammalian homolog of cdc48, is tyrosine
phosphorylated in response to T cell antigen receptor activation. EMBO
J. 11: 3533-3540, 1992.
6. Haubenberger, D.; Bittner, R. E.; Rauch-Shorny, S.; Zimprich, F.;
Mannhalter, C.; Wagner, L.; Mineva, I.; Vass, K.; Auff, E.; Zimprich,
A.: Inclusion body myopathy and Paget disease is linked to a novel
mutation in the VCP gene. Neurology 65: 1304-1305, 2005.
7. Higashiyama, H.; Hirose, F.; Yamaguchi, M.; Inoue, Y. H.; Fujikake,
N.; Matsukage, A.; Kakizuka, A.: Identification of ter94, Drosophila
VCP, as a modulator of polyglutamine-induced neurodegeneration. Cell
Death Differ. 9: 264-273, 2002.
8. Hoyle, J.; Tan, K. H.; Fisher, E. M. C.: Mapping the valosin-containing
protein (VCP) gene on human chromosome 9 and mouse chromosome 4, and
a likely pseudogene on the mouse X chromosome. Mammalian Genome 8:
778-780, 1997.
9. Johnson, J. O.; Mandrioli, J.; Benatar, M.; Abramzon, Y.; Van Deerlin,
V. M.; Trojanowski, J. Q.; Gibbs, J. R.; Brunetti, M.; Gronka, S.;
Wuu, J.; Ding, J.; McCluskey, L.; and 25 others: Exome sequencing
reveals VCP mutations as a cause of familial ALS. Neuron 68: 857-864,
2010. Note: Erratum: Neuron 69: 397 only, 2011.
10. Ju, J.-S.; Miller, S. E.; Hanson, P. I.; Weihl, C. C.: Impaired
protein aggregate handling and clearance underlie the pathogenesis
of p97/VCP-associated disease. J. Biol. Chem. 283: 30289-30299,
2008.
11. Kim, E.-J.; Park, Y.-E.; Kim, D.-S.; Ahn, B.-Y.; Kim, H.-S.; Chang,
Y. H.; Kim, S.-J,; Kim, H.-J.; Lee, H.-W.; Seeley, W. W.; Kim, S.
: Inclusion body myopathy with Paget disease of bone and frontotemporal
dementia linked to VCP p.Arg155Cys in a Korean family. Arch. Neurol. 68:
787-796, 2011.
12. Kittler, R.; Putz, G.; Pelletier, L.; Poser, I.; Heninger, A.-K.;
Drechsel, D.; Fischer, S.; Konstantinova, I.; Habermann, B.; Grabner,
H.; Yaspo, M.-L.; Himmelbauer, H.; Korn, B.; Neugebauer, K.; Pisabarro,
M. T.; Buchholz, F.: An endoribonuclease-prepared siRNA screen in
human cells identifies genes essential for cell division. Nature 432:
1036-1040, 2004.
13. Koller, K. J.; Brownstein, M. J.: Use of a cDNA clone to identify
a supposed precursor protein containing valosin. Nature 325: 542-545,
1987.
14. Mehta, S. G.; Khare, M.; Ramani, R.; Watts, G. D. J.; Simon, M.;
Osann, K. E.; Donkervoort, S.; Dec, E.; Nalbandian, A.; Platt, J.;
Pasquali, M.; Wang, A.; Mozaffar, T.; Smith, C. D.; Kimonis, V. E.
: Genotype-phenotype studies of VCP-associated inclusion body myopathy
with Paget disease of bone and/or frontotemporal dementia. Clin.
Genet. 83: 422-431, 2013.
15. Mueller, B.; Klemm, E. J.; Spooner, E.; Claessen, J. H.; Ploegh,
H. L.: SEL1L nucleates a protein complex required for dislocation
of misfolded glycoproteins. Proc. Nat. Acad. Sci. 105: 12325-12330,
2008.
16. Pleasure, I. T.; Black, M. M.; Keen, J. H.: Valosin-containing
protein, VCP, is a ubiquitous clathrin-binding protein. Nature 365:
459-462, 1993.
17. Ramadan, K.; Bruderer, R.; Spiga, F. M.; Popp, O.; Baur, T.; Gotta,
M.; Meyer, H. H.: Cdc48/p97 promotes reformation of the nucleus by
extracting the kinase Aurora B from chromatin. Nature 450: 1258-1262,
2007.
18. Sacconi, S.; Camano, P.; de Greef, J. C.; Lemmers, R. J. L. F.;
Salviati, L.; Boileau, P.; Lopez de Munain Arregui, A.; van der Maarel,
S. M.; Desnuelle, C.: Patients with a phenotype consistent with facioscapulohumeral
muscular dystrophy display genetic and epigenetic heterogeneity. J.
Med. Genet. 49: 41-46, 2012.
19. Tucker, W. S., Jr.; Hubbard, W. H.; Stryker, T. D.; Morgan, S.
W.; Evans, O. B.; Freemon, F. R.; Theil, G. B.: A new familial disorder
of combined lower motor neuron degeneration and skeletal disorganization. Trans.
Assoc. Am. Phys. 95: 126-134, 1982.
20. Uchiyama, K.; Totsukawa, G.; Puhka, M.; Kaneko, Y.; Jokitalo,
E.; Dreveny, I.; Beuron, F.; Zhang, X.; Freemont, P.; Kondo, H.:
p37 is a p97 adaptor required for Golgi and ER biogenesis in interphase
and at the end of mitosis. Dev. Cell 11: 803-816, 2006.
21. van der Zee, J.; Pirici, D.; Van Langenhove, T.; Engelborghs,
S.; Vandenberghe, R.; Hoffmann, M.; Pusswald, G.; Van den Broeck,
M.; Peeters, K.; Mattheijssens, M.; Martin, J.-J.; De Deyn, P. P.;
Cruts, M.; Haubenberger, D.; Kumar-Singh, S.; Zimprich, A.; Van Broeckhoven,
C.: Clinical heterogeneity in 3 unrelated families linked to VCP
p.Arg159His. Neurology 73: 626-632, 2009.
22. Viassolo, V.; Previtali, S. C.; Schiatti, E.; Magnani, G.; Minetti,
C.; Zara, F.; Grasso, M.; Dagna-Bricarelli, F.; Di Maria, E.: Inclusion
body myopathy, Paget's disease of the bone and frontotemporal dementia:
recurrence of the VCP R155H mutation in an Italian family and implications
for genetic counselling. Clin. Genet. 74: 54-60, 2008.
23. Watts, G. D. J.; Wymer, J.; Kovach, M. J.; Mehta, S. G.; Mumm,
S.; Darvish, D.; Pestronk, A.; Whyte, M. P.; Kimonis, V. E.: Inclusion
body myopathy associated with Paget disease of bone and frontotemporal
dementia is caused by mutant valosin-containing protein. Nature Genet. 36:
377-381, 2004.
24. Weihl, C. C.; Dalal, S.; Pestronk, A.; Hanson, P. I.: Inclusion
body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated
degradation. Hum. Molec. Genet. 15: 189-199, 2006.
25. Weihl, C. C.; Miller, S. E.; Hanson, P. I.; Pestronk, A.: Transgenic
expression of inclusion body myopathy associated mutant p97/VCP causes
weakness and ubiquitinated protein inclusions in mice. Hum. Molec.
Genet. 16: 919-928, 2007.
26. Weihl, C. C.; Pestronk, A.; Kimonis, V. E.: Valosin-containing
protein disease: Inclusion body myopathy with Paget's disease of the
bone and fronto-temporal dementia. Neuromusc. Disord. 19: 308-315,
2009.
27. Ye, Y.; Meyer, H. H.; Rapoport, T. A.: The AAA ATPase Cdc48/p97
and its partners transport proteins from the ER into the cytosol. Nature 414:
652-656, 2001.
28. Ye, Y.; Shibata, Y.; Yun, C.; Ron, D.; Rapoport, T. A.: A membrane
protein complex mediates retro-translocation from the ER lumen into
the cytosol. Nature 429: 841-847, 2004.
29. Zhang, S.-H.; Liu, J.; Kobayashi, R.; Tonks, N. K.: Identification
of the cell cycle regulator VCP (p97/CDC48) as a substrate of the
band 4.1-related protein-tyrosine phosphatase PTPH1. J. Biol. Chem. 274:
17806-17812, 1999.
*FIELD* CN
Cassandra L. Kniffin - updated: 1/6/2014
Cassandra L. Kniffin - updated: 12/17/2013
Patricia A. Hartz - updated: 5/31/2013
Cassandra L. Kniffin - updated: 4/25/2012
Cassandra L. Kniffin - updated: 12/8/2011
George E. Tiller - updated: 12/1/2011
Cassandra L. Kniffin - updated: 5/5/2011
Cassandra L. Kniffin - updated: 12/21/2009
Patricia A. Hartz - updated: 11/10/2009
Cassandra L. Kniffin - updated: 10/29/2009
Cassandra L. Kniffin - updated: 4/23/2009
Cassandra L. Kniffin - updated: 3/23/2009
Ada Hamosh - updated: 1/24/2008
Cassandra L. Kniffin - updated: 2/5/2007
Patricia A. Hartz - updated: 1/4/2007
Ada Hamosh - updated: 3/8/2005
Ada Hamosh - updated: 7/22/2004
Ada Hamosh - updated: 4/2/2004
Paul J. Converse - updated: 1/28/2002
Ada Hamosh - updated: 1/2/2002
Victor A. McKusick - updated: 10/14/1997
*FIELD* CD
Alan F. Scott: 1/30/1996
*FIELD* ED
carol: 01/07/2014
ckniffin: 1/6/2014
carol: 12/19/2013
mcolton: 12/18/2013
ckniffin: 12/17/2013
mgross: 9/17/2013
carol: 7/26/2013
mgross: 5/31/2013
carol: 4/26/2012
ckniffin: 4/25/2012
carol: 12/16/2011
ckniffin: 12/8/2011
alopez: 12/5/2011
terry: 12/1/2011
carol: 7/6/2011
terry: 6/3/2011
carol: 6/1/2011
wwang: 5/18/2011
ckniffin: 5/5/2011
carol: 7/30/2010
wwang: 1/14/2010
ckniffin: 12/21/2009
terry: 12/1/2009
mgross: 11/10/2009
wwang: 11/5/2009
ckniffin: 10/29/2009
wwang: 5/13/2009
ckniffin: 4/23/2009
wwang: 4/7/2009
ckniffin: 3/23/2009
alopez: 2/5/2008
terry: 1/24/2008
carol: 5/10/2007
wwang: 2/9/2007
ckniffin: 2/5/2007
mgross: 1/4/2007
wwang: 8/9/2006
alopez: 3/8/2005
carol: 1/13/2005
terry: 11/3/2004
alopez: 7/23/2004
terry: 7/22/2004
alopez: 4/6/2004
terry: 4/2/2004
mgross: 1/28/2002
alopez: 1/8/2002
terry: 1/2/2002
mgross: 3/21/2000
mark: 10/17/1997
terry: 10/14/1997
terry: 7/28/1997
mark: 4/8/1997
terry: 3/26/1996
mark: 1/30/1996
*RECORD*
*FIELD* NO
601023
*FIELD* TI
*601023 VALOSIN-CONTAINING PROTEIN; VCP
;;CDC48, YEAST, HOMOLOG OF;;
p97
*FIELD* TX
read more
DESCRIPTION
The VCP gene encodes valosin-containing protein, a ubiquitously
expressed multifunctional protein that is a member of the AAA+ (ATPase
associated with various activities) protein family. It has been
implicated in multiple cellular functions ranging from organelle
biogenesis to ubiquitin-dependent protein degradation (summary by Weihl
et al., 2009).
CLONING
Clathrin is a structural protein found in coated pits and vesicles,
organelles which are important in membrane trafficking functions such as
endocytosis and Golgi sorting. A 100-kD protein, designated
valosin-containing protein or VCP by early investigators, is a
structural protein complexed with clathrin (see 118960). VCP is the
homolog of yeast cdc48p, and is a member of a family that includes
putative ATP-binding proteins involved in vesicle transport and fusion,
26S proteasome function, and assembly of peroxisomes (Pleasure et al.,
1993). VCP was cloned from the pig (Koller and Brownstein, 1987) and
mouse (Egerton et al., 1992). Druck et al. (1995) cloned a portion of
the human cDNA.
Cloutier et al. (2013) stated that the deduced 806-amino acid VCP
protein contains an N-terminal domain, followed by a linker region, an
ATPase domain, a second linker region, a second ATPase domain, and a
C-terminal domain. The N-terminal domain consists of a double-psi-barrel
superfold and 4-stranded beta barrel, and each ATPase domain consists of
Walker A and B motifs and a 4-alpha-helix bundle. VCP is extensively
modified by phosphorylation and acetylation, as well as by lysine
methylation.
GENE STRUCTURE
Johnson et al. (2010) noted that the VCP gene contains 17 exons.
MAPPING
Druck et al. (1995) used a partial human VCP cDNA to probe a panel of
somatic cell hybrid DNAs and mapped the VCP gene to chromosome
9pter-q34.
By database analysis, Hoyle et al. (1997) identified a human expressed
sequence tag (EST) that shares 80% identity with the mouse 3-prime
untranslated region. They designed primers to this EST and amplified and
sequenced a 127-bp product from total human DNA. This product detected 1
fragment only in a HindIII digest of total human DNA, indicating there
is only 1 VCP sequence in the human genome. Using the 127-bp sequence to
screen a human PAC library, followed by FISH analysis, they mapped the
VCP gene to chromosome 9p13-p12. They mapped the mouse Vcp gene to mouse
chromosome 4 and found a probable pseudogene on the mouse X chromosome.
The VCP gene maps to chromosome 9p13.3 (Johnson et al., 2010).
GENE FUNCTION
Ye et al. (2001) demonstrated that VCP (CDC48 in yeast and p97 in
mammals) is required for the export of endoplasmic reticulum (ER) into
the cytosol. Whereas CDC48/p97 was known to function in a complex with
the cofactor p47 in membrane fusion, Ye et al. (2001) demonstrated that
its role in ER protein export requires the interacting partners UFD1
(601754) and NPL4 (606590). The AAA ATPase interacts with substrates at
the ER membrane and is needed to release them as polyubiquitinated
species into the cytosol.
Zhang et al. (1999) created a substrate-trapping mutant of PTPH1
(176877) that interacted primarily with VCP in vitro but not in cells. A
double mutant of PTPH1 had a marked reduction in phosphotyrosine
content, specifically trapped VCP in vivo, and recognized the C-terminal
tyrosines of VCP. Immunoblot analysis showed that wildtype PTPH1
specifically dephosphorylated VCP. Zhang et al. (1999) concluded that
PTPH1 exerts its effects on cell growth through dephosphorylation of VCP
and that tyrosine phosphorylation is an important regulator of VCP
function.
Watts et al. (2004) summarized that VCP has been associated with several
essential cell protein pathways including cell cycle, homotypic membrane
fusion, nuclear envelope reconstruction, postmitotic Golgi reassembly,
DNA damage response, suppressor of apoptosis, and ubiquitin-dependent
protein degradation. Higashiyama et al. (2002) identified a fruit fly
VCP loss-of-function mutant as a dominant suppressor of expanded
polyglutamine-induced neuronal degeneration. The suppressive effects of
the loss-of-function mutant did not seem to result from inhibition of
polyglutamine aggregate formation but rather from the degree of loss of
VCP function. This suggested that a gene dosage response for VCP
expression is essential to its function in expanded
polyglutamine-induced neuronal degeneration. In support of this idea,
transgenic fruit flies in which VCP levels were elevated experienced
severe apoptotic cell death, whereas homozygous VCP loss-of-function
mutants were embryonic lethal.
Ye et al. (2004) found that VIMP (607918) recruits the p97 ATPase (VCP)
and its cofactor, the UFD1/NPL4 complex, to the ER for
retrotranslocation of misfolded proteins into the cytosol. They noted
that all pathways of retrotranslocation appear to require the function
of the p97 ATPase complex, which may provide the general driving force
for the movement of proteins into the cytosol.
Using a library of endoribonuclease-prepared short interfering RNAs
(esiRNAs), Kittler et al. (2004) identified 37 genes required for cell
division, one of which was VCP. These 37 genes included several splicing
factors for which knockdown generates mitotic spindle defects. In
addition, a putative nuclear-export terminator was found to speed up
cell proliferation and mitotic progression after knockdown.
Uchiyama et al. (2006) found that rodent p37 (610686) formed a complex
with p97 in cytosol and localized to Golgi and ER. Small interfering RNA
experiments in HeLa cells revealed that p37 was required for Golgi and
ER biogenesis. Injection of anti-p37 antibodies into HeLa cells at
different stages of the cell cycle showed that p37 was involved in Golgi
and ER maintenance during interphase and in their reassembly at the end
of mitosis. In an in vitro Golgi reassembly assay, the p97/p37 complex
showed membrane fusion activity that required p115 (603344)-GM130
(GOLGA2; 602580) tethering and SNARE GS15 (BET1L; 615417). VCIP135
(VCPIP1) was also required, but its deubiquitinating activity was
unnecessary for p97/p37-mediated activities.
Ramadan et al. (2007) showed that p97 stimulates nucleus reformation by
inactivating the chromatin-associated kinase Aurora B (604970). During
mitosis, Aurora B inhibits nucleus reformation by preventing chromosome
decondensation and formation of the nuclear envelope membrane. During
exit from mitosis, p97 binds to Aurora B after its ubiquitylation and
extracts it from chromatin. This leads to inactivation of Aurora B on
chromatin, thus allowing chromatin decondensation and nuclear envelope
formation. Ramadan et al. (2007) concluded that their data revealed an
essential pathway that regulates reformation of the nucleus after
mitosis and defined ubiquitin-dependent protein extraction as a common
mechanism of Cdc48/p97 activity also during nucleus formation.
Using human cell lines, Mueller et al. (2008) identified several
components of a protein complex required for retrotranslocation or
dislocation of misfolded proteins from the ER lumen to the cytosol for
proteasome-dependent degradation. These included SEL1L (602329), HRD1
(SYVN1; 608046), derlin-2 (DERL2; 610304), the ATPase p97, PDI (P4HB;
176790), BIP (HSPA5; 138120), calnexin (CANX; 114217), AUP1 (602434),
UBXD8 (FAF2), UBC6E (UBE2J1), and OS9 (609677).
By affinity purification, SDS-PAGE, and mass spectrometry, Cloutier et
al. (2013) found that METTL21D (615260) expressed in HEK293 cells
interacted with endogenous VCP, ASPSCR1 (606236), and UBXN6 (611946). In
vitro methylation assays showed that recombinant METTL21D methylated
VCP, which was abrogated by mutation of lys315 in ATPase domain 1 of
VCP. Methylation reduced the activity of VCP ATPase domain 1, but it had
no effect on the activity of VCP ATPase domain 2. METTL21D did not
methylate ASPSRC1 or UBXN6, but the presence of ASPSRC1, but not UBXN6,
enhanced METTL21D-dependent VCP methylation.
In immunoprecipitation studies, Clemen et al. (2010) identified
strumpellin (KIAA0196; 601657) as a binding partner with VCP.
Strumpellin was detected in pathologic protein aggregates in muscle
tissue derived from patients with IBMPFD1 (167320) as well as in various
myofibrillar myopathies and in cortical neurons of a mouse model of
Huntington disease (HD; 143100). These findings suggested that
strumpellin, like VCP, may have a role in various protein aggregate
diseases.
MOLECULAR GENETICS
- Inclusion Body Myopathy With Paget Disease of Bone and Frontotemporal
Dementia
Watts et al. (2004) identified missense mutations in VCP as the cause of
inclusion body myopathy with Paget disease of bone and frontotemporal
dementia (IBMPFD; 167320). Ten of 13 families with this disorder had an
amino acid change at arginine-155, either to histidine, proline, or
cysteine. Arginine-155 of VCP was conserved in homologs through all
species examined except in 2 C. elegans homologs, which had glutamine at
that position. Arginine-191 was invariant in all species examined, and
arginine-95 was substituted by histidine in only 2 species.
Watts et al. (2004) suggested that since patients with IBMPFD are viable
with relatively late onset of disease, the mutations identified do not
disrupt the cell cycle or apoptosis pathways. They proposed that
mutations in VCP cause Paget disease of bone by compromising ubiquitin
binding and target similar cellular pathways or proteins. They suggested
that the progressive neuronal degeneration has to do with protein
quality control and ubiquitin protein degradation pathways. Finally,
Watts et al. (2004) concluded that because IBMPFD is a dominant
progressive syndrome, the mutations they identified are probably
relatively subtle and aging, oxidative stress, and endoplasmic reticulum
stress probably define a threshold at which the IBMPFD phenotype becomes
manifest.
In vitro functional expression studies by Weihl et al. (2006) showed
that cells transfected with the mutant R155H (601023.0001) and R95G
(601023.0004) proteins developed a prominent increase in diffuse and
aggregated ubiquitin conjugates and showed impaired function of
endoplasmic reticulum-associated degradation (ERAD), as well as a
distorted ER structure.
In human cells with IBMPFD-associated mutations, Ju et al. (2008) found
that treatment with a proteasome inhibitor resulted in increased cell
death and an increase in perinuclear ubiquitinated proteins, but no
clear aggresomes, compared to wildtype. Expression of an aggregate
protein in mutant cells did not result in proper formation of inclusion
bodies or aggresomes. A similar lack of inclusion body formation was
observed in mutant mouse muscle fibers in vivo. Further studies showed
that mutant VCP trapped aggregated proteins but failed to release them
to aggresomes or inclusion bodies. This was reversed upon coexpression
with HDAC6 (300272), a VCP-binding protein that facilitates formation of
aggresomes. Ju et al. (2008) concluded that mutations in the VCP gene
impaired the proper clearance of aggregated proteins.
- Amyotrophic Lateral Sclerosis 14, With or Without Frontotemporal
Dementia
Using exome sequencing, Johnson et al. (2010) identified a heterozygous
mutation in the VCP gene (R191Q; 601023.0006) in 4 affected members of
an Italian family with amyotrophic lateral sclerosis-14 (ALS14; 613954)
with or without frontotemporal dementia. Screening of the VCP gene in
210 familial ALS cases and 78 autopsy-proven ALS cases identified 3
additional pathogenic VCP mutations (601023.0001; 601012.0008, and
601023.0009) in 4 patients. The findings expanded the phenotype
associated with VCP mutations to include classic ALS.
- Functional Effects of VCP Mutations
Cloutier et al. (2013) found that the R155H (601023.0001), R159G
(601023.0007), and R191Q (601023.0006) mutations in VCP did not alter in
vitro methylation of VCP by METTL21D. However, ASPSRC1 did not enhance
methylation of VCP containing these mutations, as it did with wildtype
VCP.
GENOTYPE/PHENOTYPE CORRELATIONS
Mehta et al. (2013) analyzed clinical and biochemical markers from a
database of 190 individuals from 27 families harboring 10 missense
mutations in the VCP gene. Among these, 145 mutation carriers were
symptomatic and 45 were presymptomatic. The most common clinical feature
(in 91% of patients) was onset of myopathic weakness at a mean age of 43
years. Paget disease of the bone was found in 52% of patients at a mean
age of 41 years. Frontotemporal dementia occurred in 30% of patients at
a mean age of 55 years. Significant genotype-phenotype correlations were
difficult to establish because of small numbers. However, patients with
the R155C mutation (60123.0002) had a more severe phenotype with an
earlier onset of myopathy and Paget disease, as well as decreased
survival, compared to those with the R155H mutation (601023.0001). A
diagnosis of ALS was found in at least 13 (8.9%) individuals from the 27
families, including 10 patients with the R155H mutation, and 5 (3%)
patients were diagnosed with Parkinson disease.
ANIMAL MODEL
Weihl et al. (2007) found that transgenic mice overexpressing the R155H
mutation became progressively weaker in a dose-dependent manner starting
at 6 months of age. There was abnormal muscle pathology, with coarse
internal architecture, vacuolation, and disorganized membrane morphology
with reduced caveolin-3 (CAV3; 601253) expression at the sarcolemma.
Even before animals displayed measurable weakness, there was an increase
in ubiquitin-containing protein inclusions and high molecular weight
ubiquitinated proteins. These findings suggested a dysregulation in
protein degradation.
Custer et al. (2010) developed and characterized transgenic mice with
ubiquitous expression of wildtype and disease-causing versions of human
VCP/p97. Mice expressing VCP/p97 harboring the mutations R155H
(601023.0001) or A232E (601023.0003) exhibited progressive muscle
weakness, and developed inclusion body myopathy including rimmed
vacuoles and TDP43 (605078) pathology. The brain showed widespread TDP43
pathology, and the skeleton exhibited severe osteopenia accompanied by
focal lytic and sclerotic lesions in vertebrae and femur. In vitro
studies indicated that mutant VCP caused inappropriate activation of the
NF-kappa-B (see 164011) signaling cascade, which could contribute to the
mechanism of pathogenesis in multiple tissues including muscle, bone,
and brain.
*FIELD* AV
.0001
INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL
DEMENTIA
AMYOTROPHIC LATERAL SCLEROSIS 14 WITHOUT FRONTOTEMPORAL DEMENTIA,
INCLUDED
VCP, ARG155HIS
In 7 of 13 families with autosomal dominant IBMPFD (167320), Watts et
al. (2004) identified a G-to-A transition at nucleotide 464 of the VCP
gene, resulting in an arg155-to-his substitution (R155H). This mutation
appears to have arisen independently on several haplotype backgrounds.
Viassolo et al. (2008) identified heterozygosity for the R155H mutation
in 3 affected members of an Italian family with IBMPFD. All 3 had
progressive inclusion body myopathy and rapidly progressive severe
dementia, but only 1 developed Paget disease.
In vitro functional expression studies by Weihl et al. (2006) showed
that R155H-mutant protein properly assembled into a hexameric structure
and showed normal ATPase activity. Cell transfected with the mutant
protein showed a prominent increase in diffuse and aggregated ubiquitin
conjugates and impaired function of endoplasmic reticulum-associated
degradation (ERAD), as well as a distorted ER structure.
Johnson et al. (2010) identified heterozygosity for the R155H mutation,
which they stated resulted from an 853G-A transition in exon 5, in a
member of the family reported by Watts et al. (2004). However, the
family member reported by Johnson et al. (2010) had classic ALS (ALS14;
613954) without evidence of Paget disease, myopathy, or frontotemporal
dementia. Postmortem examination of this patient showed loss of
brainstem and spinal cord motor neurons with Bunina bodies in surviving
neurons, TDP43 (TARDBP; 605078)-positive immunostaining, and mild pallor
of the lateral descending corticospinal tracts, all features consistent
with diagnosis of ALS. The findings expanded the phenotype associated
with VCP mutations, even within a single family.
.0002
INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL
DEMENTIA
VCP, ARG155CYS
In 2 of 13 families with autosomal dominant IBMPFD (167320), Watts et
al. (2004) identified a C-to-T transition at nucleotide 463 of the VCP
gene, resulting in an arg155-to-cys substitution (R155C).
Kim et al. (2011) identified a heterozygous R155C mutation in 3 Korean
sibs with IBMPFD. The proband developed progressive dementia presenting
as fluent aphasia and language difficulties with onset at age 47. She
never developed myopathy, but did develop asymptomatic Paget disease
with increased serum alkaline phosphatase and lytic bone lesions on
imaging. Her brother developed slowly progressive proximal muscle
weakness at age 50, followed by frontotemporal dementia characterized
initially by comprehension defects at age 54. He never had Paget
disease, although serum alkaline phosphatase was increased. A second
brother developed muscle weakness at age 47, followed by Paget disease
at age 53, and dementia at age 61. Brain MRI in all patients showed
asymmetric atrophy in the anterior inferior and lateral temporal lobes
and inferior parietal lobule with ventricular dilatation on the affected
side (2 on the left, 1 on the right). Two had glucose hypometabolism in
the lateral temporal and inferior parietal areas, with less involvement
of the anterior temporal and frontal lobes compared to those with
typical semantic dementia.
.0003
INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL
DEMENTIA
VCP, ALA232GLU
In 1 of 13 families with autosomal dominant IBMPFD (167320), Watts et
al. (2004) identified a C-to-A transversion at nucleotide 695 of the VCP
gene, resulting in an ala-to-glu change at codon 232 (A232E).
.0004
INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL
DEMENTIA
VCP, ARG95GLY
In 1 of 13 families with autosomal dominant IBMPFD (167320), Watts et
al. (2004) identified a C-to-G transversion at nucleotide 283 of the VCP
gene, resulting in an arg-to-gly substitution at codon 95 (R95G).
In vitro functional expression studies by Weihl et al. (2006) showed
that cells transfected with R95G-mutant protein developed a prominent
increased in diffuse and aggregated ubiquitin conjugates and impaired
function of endoplasmic reticulum-associated degradation (ERAD), as well
as a distorted ER structure.
.0005
INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL
DEMENTIA
VCP, ARG155PRO
In 1 of 13 families with autosomal dominant IBMPFD (167320), Watts et
al. (2004) identified a G-to-C transversion at nucleotide 464 of the VCP
gene, resulting in an arg-to-pro substitution at codon 155 (R155P). This
family was originally reported by Tucker et al. (1982).
.0006
INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL
DEMENTIA
AMYOTROPHIC LATERAL SCLEROSIS 14 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA,
INCLUDED
VCP, ARG191GLN
In 1 of 13 families with autosomal dominant IBMPFD (167320), Watts et
al. (2004) identified a G-to-C transversion at nucleotide 572 of the VCP
gene, resulting in an arg-to-gln substitution at codon 191 (R191Q).
Using exome sequencing, Johnson et al. (2010) identified heterozygosity
for the R191Q mutation in the VCP gene, which they stated resulted from
a 961G-A transition in exon 5, in 4 affected members of an Italian
family with amyotrophic lateral sclerosis-14 (ALS14; 613954). Affected
individuals presented in adulthood with limb-onset motor neuron symptoms
that rapidly progressed to involve all 4 limbs and the bulbar
musculature, consistent with a classical ALS phenotype. All patients had
unequivocal upper and lower motor signs, and none had evidence of Paget
disease. One patient showed mild frontotemporal dementia. Autopsy
material was not available. A parent of the proband had died at age 58
with dementia, parkinsonism, Paget disease, and upper limb weakness,
suggesting IBMPFD. The findings indicated an expanded phenotypic
spectrum for VCP mutations.
Sacconi et al. (2012) identified a heterozygous R191Q mutation in 2
unrelated men in their fifties who presented with a phenotype
reminiscent of FSHD1 (158900). One had scapuloperoneal weakness without
facial involvement and increased serum creatine kinase. The second
patient had facial weakness, shoulder and pelvic girdle weakness, and
anterior foreleg weakness. Creatine kinase was increased 4-fold. Muscle
biopsies of both patients showed mild dystrophic changes, but no
inclusion bodies. EMG showed myopathic patterns. One patient was later
found to have a mild dysexecutive syndrome, but neither had evidence of
Paget disease.
.0007
INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL
DEMENTIA
VCP, ARG159HIS
In 4 affected sibs of an Austrian family with autosomal dominant
inclusion body myopathy and Paget disease but without dementia (167320),
Haubenberger et al. (2005) identified a heterozygous 688G-A transition
in exon 5 of the VCP gene, resulting in an arg159-to-his (R159H)
substitution. The mutation occurred in a highly conserved region close
to the codon 155 hotspot described by Watts et al. (2004) and was not
present in 384 control chromosomes. None of the 4 affected sibs
demonstrated frontotemporal dementia even though all were over 60 years
of age. Haubenberger et al. (2005) noted that only approximately 30% of
patients with VCP mutations develop dementia, illustrating phenotypic
variability. In a follow-up of this family, van der Zee et al. (2009)
noted that 1 patient had developed dementia at age 64. Van der Zee et
al. (2009) also identified the R159H mutation in affected members of 2
unrelated Belgian families. In 1 family, patients presented with
frontotemporal lobar degeneration only, whereas in the other family,
patients developed frontotemporal lobar degeneration, Paget disease of
the bone, or both without signs of inclusion body myopathy for any of
the mutation carriers. Haplotype analysis showed that the 2 families and
the Austrian family reported by Haubenberger et al. (2005) were
unrelated. Autopsy data of 3 patients from the 2 Belgian families showed
frontotemporal lobar degeneration with numerous
ubiquitin-immunoreactive, intranuclear inclusions and dystrophic
neurites staining positive for TDP43 (TARDBP; 605078) protein. Van der
Zee et al. (2009) commented on the high degree of clinical heterogeneity
and incomplete penetrance of the disorder in different families carrying
the same mutation.
.0008
AMYOTROPHIC LATERAL SCLEROSIS 14 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
VCP, ARG159GLY
In affected members of a family with ALS14 with or without
frontotemporal dementia (613954), Johnson et al. (2010) identified a
heterozygous 864C-G transversion in exon 5 of the VCP gene, resulting in
an arg159-to-gly (R159G) substitution in a conserved residue. The
mutation was not found in 3,138 control chromosomes, and a different
pathogenic mutation had previously been reported in this codon (R159H;
601023.0007). Two patients had classic ALS with frontotemporal dementia,
and a third obligate mutation carrier had Paget disease, followed by ALS
without cognitive impairment.
.0009
AMYOTROPHIC LATERAL SCLEROSIS 14 WITHOUT FRONTOTEMPORAL DEMENTIA
VCP, ASP592ASN
In a patient with ALS14 without frontotemporal dementia (613954),
Johnson et al. (2010) identified a heterozygous 2163G-A transition in
exon 14 of the VCP gene, resulting in an asp592-to-asn (D592N)
substitution in a residue directly adjacent to the central pore formed
by the VCP hexamer. The mutation was not found in 3,138 control
chromosomes. A maternal uncle had previously been diagnosed with ALS.
*FIELD* RF
1. Clemen, C. S.; Tangavelou, K.; Strucksberg, K.-H.; Just, S.; Gaertner,
L.; Regus-Leidig, H.; Stumpf, M.; Reimann, J.; Coras, R.; Morgan,
R. O.; Fernandez, M.-P.; Hofmann, A.; Muller, S.; Schoser, B.; Hanisch,
F.-G.; Rottbauer, W.; Blumcke, I.; von Horsten, S.; Eichinger, L.;
Schroder, R.: Strumpellin is a novel valosin-containing protein binding
partner linking hereditary spastic paraplegia to protein aggregation
diseases. Brain 133: 2920-2941, 2010.
2. Cloutier, P.; Lavallee-Adam, M.; Faubert, D.; Blanchette, M.; Coulombe,
B.: A newly uncovered group of distantly related lysine methyltransferases
preferentially interact with molecular chaperones to regulate their
activity. PLoS Genet. 9: e1003210, 2013. Note: Electronic Article.
3. Custer, S. K.; Neumann, M.; Lu, H.; Wright, A. C.; Taylor, J. P.
: Transgenic mice expressing mutant forms VCP/p97 recapitulate the
full spectrum of IBMPFD including degeneration in muscle, brain and
bone. Hum. Molec. Genet. 19: 1741-1755, 2010.
4. Druck, T.; Gu, Y.; Prabhala. G.; Cannizzaro, L. A.; Park, S.-H.;
Huebner, K.; Keen, J. H.: Chromosome localization of human genes
for clathrin adaptor polypeptides AP2-beta and AP50 and the clathrin-binding
protein, VCP. Genomics 30: 94-97, 1995.
5. Egerton, M.; Ashe, O. R.; Chen, D.; Druker, B. J.; Burgess, W.
H.; Samelson, L. E.: VCP, the mammalian homolog of cdc48, is tyrosine
phosphorylated in response to T cell antigen receptor activation. EMBO
J. 11: 3533-3540, 1992.
6. Haubenberger, D.; Bittner, R. E.; Rauch-Shorny, S.; Zimprich, F.;
Mannhalter, C.; Wagner, L.; Mineva, I.; Vass, K.; Auff, E.; Zimprich,
A.: Inclusion body myopathy and Paget disease is linked to a novel
mutation in the VCP gene. Neurology 65: 1304-1305, 2005.
7. Higashiyama, H.; Hirose, F.; Yamaguchi, M.; Inoue, Y. H.; Fujikake,
N.; Matsukage, A.; Kakizuka, A.: Identification of ter94, Drosophila
VCP, as a modulator of polyglutamine-induced neurodegeneration. Cell
Death Differ. 9: 264-273, 2002.
8. Hoyle, J.; Tan, K. H.; Fisher, E. M. C.: Mapping the valosin-containing
protein (VCP) gene on human chromosome 9 and mouse chromosome 4, and
a likely pseudogene on the mouse X chromosome. Mammalian Genome 8:
778-780, 1997.
9. Johnson, J. O.; Mandrioli, J.; Benatar, M.; Abramzon, Y.; Van Deerlin,
V. M.; Trojanowski, J. Q.; Gibbs, J. R.; Brunetti, M.; Gronka, S.;
Wuu, J.; Ding, J.; McCluskey, L.; and 25 others: Exome sequencing
reveals VCP mutations as a cause of familial ALS. Neuron 68: 857-864,
2010. Note: Erratum: Neuron 69: 397 only, 2011.
10. Ju, J.-S.; Miller, S. E.; Hanson, P. I.; Weihl, C. C.: Impaired
protein aggregate handling and clearance underlie the pathogenesis
of p97/VCP-associated disease. J. Biol. Chem. 283: 30289-30299,
2008.
11. Kim, E.-J.; Park, Y.-E.; Kim, D.-S.; Ahn, B.-Y.; Kim, H.-S.; Chang,
Y. H.; Kim, S.-J,; Kim, H.-J.; Lee, H.-W.; Seeley, W. W.; Kim, S.
: Inclusion body myopathy with Paget disease of bone and frontotemporal
dementia linked to VCP p.Arg155Cys in a Korean family. Arch. Neurol. 68:
787-796, 2011.
12. Kittler, R.; Putz, G.; Pelletier, L.; Poser, I.; Heninger, A.-K.;
Drechsel, D.; Fischer, S.; Konstantinova, I.; Habermann, B.; Grabner,
H.; Yaspo, M.-L.; Himmelbauer, H.; Korn, B.; Neugebauer, K.; Pisabarro,
M. T.; Buchholz, F.: An endoribonuclease-prepared siRNA screen in
human cells identifies genes essential for cell division. Nature 432:
1036-1040, 2004.
13. Koller, K. J.; Brownstein, M. J.: Use of a cDNA clone to identify
a supposed precursor protein containing valosin. Nature 325: 542-545,
1987.
14. Mehta, S. G.; Khare, M.; Ramani, R.; Watts, G. D. J.; Simon, M.;
Osann, K. E.; Donkervoort, S.; Dec, E.; Nalbandian, A.; Platt, J.;
Pasquali, M.; Wang, A.; Mozaffar, T.; Smith, C. D.; Kimonis, V. E.
: Genotype-phenotype studies of VCP-associated inclusion body myopathy
with Paget disease of bone and/or frontotemporal dementia. Clin.
Genet. 83: 422-431, 2013.
15. Mueller, B.; Klemm, E. J.; Spooner, E.; Claessen, J. H.; Ploegh,
H. L.: SEL1L nucleates a protein complex required for dislocation
of misfolded glycoproteins. Proc. Nat. Acad. Sci. 105: 12325-12330,
2008.
16. Pleasure, I. T.; Black, M. M.; Keen, J. H.: Valosin-containing
protein, VCP, is a ubiquitous clathrin-binding protein. Nature 365:
459-462, 1993.
17. Ramadan, K.; Bruderer, R.; Spiga, F. M.; Popp, O.; Baur, T.; Gotta,
M.; Meyer, H. H.: Cdc48/p97 promotes reformation of the nucleus by
extracting the kinase Aurora B from chromatin. Nature 450: 1258-1262,
2007.
18. Sacconi, S.; Camano, P.; de Greef, J. C.; Lemmers, R. J. L. F.;
Salviati, L.; Boileau, P.; Lopez de Munain Arregui, A.; van der Maarel,
S. M.; Desnuelle, C.: Patients with a phenotype consistent with facioscapulohumeral
muscular dystrophy display genetic and epigenetic heterogeneity. J.
Med. Genet. 49: 41-46, 2012.
19. Tucker, W. S., Jr.; Hubbard, W. H.; Stryker, T. D.; Morgan, S.
W.; Evans, O. B.; Freemon, F. R.; Theil, G. B.: A new familial disorder
of combined lower motor neuron degeneration and skeletal disorganization. Trans.
Assoc. Am. Phys. 95: 126-134, 1982.
20. Uchiyama, K.; Totsukawa, G.; Puhka, M.; Kaneko, Y.; Jokitalo,
E.; Dreveny, I.; Beuron, F.; Zhang, X.; Freemont, P.; Kondo, H.:
p37 is a p97 adaptor required for Golgi and ER biogenesis in interphase
and at the end of mitosis. Dev. Cell 11: 803-816, 2006.
21. van der Zee, J.; Pirici, D.; Van Langenhove, T.; Engelborghs,
S.; Vandenberghe, R.; Hoffmann, M.; Pusswald, G.; Van den Broeck,
M.; Peeters, K.; Mattheijssens, M.; Martin, J.-J.; De Deyn, P. P.;
Cruts, M.; Haubenberger, D.; Kumar-Singh, S.; Zimprich, A.; Van Broeckhoven,
C.: Clinical heterogeneity in 3 unrelated families linked to VCP
p.Arg159His. Neurology 73: 626-632, 2009.
22. Viassolo, V.; Previtali, S. C.; Schiatti, E.; Magnani, G.; Minetti,
C.; Zara, F.; Grasso, M.; Dagna-Bricarelli, F.; Di Maria, E.: Inclusion
body myopathy, Paget's disease of the bone and frontotemporal dementia:
recurrence of the VCP R155H mutation in an Italian family and implications
for genetic counselling. Clin. Genet. 74: 54-60, 2008.
23. Watts, G. D. J.; Wymer, J.; Kovach, M. J.; Mehta, S. G.; Mumm,
S.; Darvish, D.; Pestronk, A.; Whyte, M. P.; Kimonis, V. E.: Inclusion
body myopathy associated with Paget disease of bone and frontotemporal
dementia is caused by mutant valosin-containing protein. Nature Genet. 36:
377-381, 2004.
24. Weihl, C. C.; Dalal, S.; Pestronk, A.; Hanson, P. I.: Inclusion
body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated
degradation. Hum. Molec. Genet. 15: 189-199, 2006.
25. Weihl, C. C.; Miller, S. E.; Hanson, P. I.; Pestronk, A.: Transgenic
expression of inclusion body myopathy associated mutant p97/VCP causes
weakness and ubiquitinated protein inclusions in mice. Hum. Molec.
Genet. 16: 919-928, 2007.
26. Weihl, C. C.; Pestronk, A.; Kimonis, V. E.: Valosin-containing
protein disease: Inclusion body myopathy with Paget's disease of the
bone and fronto-temporal dementia. Neuromusc. Disord. 19: 308-315,
2009.
27. Ye, Y.; Meyer, H. H.; Rapoport, T. A.: The AAA ATPase Cdc48/p97
and its partners transport proteins from the ER into the cytosol. Nature 414:
652-656, 2001.
28. Ye, Y.; Shibata, Y.; Yun, C.; Ron, D.; Rapoport, T. A.: A membrane
protein complex mediates retro-translocation from the ER lumen into
the cytosol. Nature 429: 841-847, 2004.
29. Zhang, S.-H.; Liu, J.; Kobayashi, R.; Tonks, N. K.: Identification
of the cell cycle regulator VCP (p97/CDC48) as a substrate of the
band 4.1-related protein-tyrosine phosphatase PTPH1. J. Biol. Chem. 274:
17806-17812, 1999.
*FIELD* CN
Cassandra L. Kniffin - updated: 1/6/2014
Cassandra L. Kniffin - updated: 12/17/2013
Patricia A. Hartz - updated: 5/31/2013
Cassandra L. Kniffin - updated: 4/25/2012
Cassandra L. Kniffin - updated: 12/8/2011
George E. Tiller - updated: 12/1/2011
Cassandra L. Kniffin - updated: 5/5/2011
Cassandra L. Kniffin - updated: 12/21/2009
Patricia A. Hartz - updated: 11/10/2009
Cassandra L. Kniffin - updated: 10/29/2009
Cassandra L. Kniffin - updated: 4/23/2009
Cassandra L. Kniffin - updated: 3/23/2009
Ada Hamosh - updated: 1/24/2008
Cassandra L. Kniffin - updated: 2/5/2007
Patricia A. Hartz - updated: 1/4/2007
Ada Hamosh - updated: 3/8/2005
Ada Hamosh - updated: 7/22/2004
Ada Hamosh - updated: 4/2/2004
Paul J. Converse - updated: 1/28/2002
Ada Hamosh - updated: 1/2/2002
Victor A. McKusick - updated: 10/14/1997
*FIELD* CD
Alan F. Scott: 1/30/1996
*FIELD* ED
carol: 01/07/2014
ckniffin: 1/6/2014
carol: 12/19/2013
mcolton: 12/18/2013
ckniffin: 12/17/2013
mgross: 9/17/2013
carol: 7/26/2013
mgross: 5/31/2013
carol: 4/26/2012
ckniffin: 4/25/2012
carol: 12/16/2011
ckniffin: 12/8/2011
alopez: 12/5/2011
terry: 12/1/2011
carol: 7/6/2011
terry: 6/3/2011
carol: 6/1/2011
wwang: 5/18/2011
ckniffin: 5/5/2011
carol: 7/30/2010
wwang: 1/14/2010
ckniffin: 12/21/2009
terry: 12/1/2009
mgross: 11/10/2009
wwang: 11/5/2009
ckniffin: 10/29/2009
wwang: 5/13/2009
ckniffin: 4/23/2009
wwang: 4/7/2009
ckniffin: 3/23/2009
alopez: 2/5/2008
terry: 1/24/2008
carol: 5/10/2007
wwang: 2/9/2007
ckniffin: 2/5/2007
mgross: 1/4/2007
wwang: 8/9/2006
alopez: 3/8/2005
carol: 1/13/2005
terry: 11/3/2004
alopez: 7/23/2004
terry: 7/22/2004
alopez: 4/6/2004
terry: 4/2/2004
mgross: 1/28/2002
alopez: 1/8/2002
terry: 1/2/2002
mgross: 3/21/2000
mark: 10/17/1997
terry: 10/14/1997
terry: 7/28/1997
mark: 4/8/1997
terry: 3/26/1996
mark: 1/30/1996
MIM
613954
*RECORD*
*FIELD* NO
613954
*FIELD* TI
#613954 AMYOTROPHIC LATERAL SCLEROSIS 14, WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA;
read moreALS14
*FIELD* TX
A number sign (#) is used with this entry because amyotrophic lateral
sclerosis-14 with or without frontotemporal dementia (ALS14) is caused
by heterozygous mutation in the VCP gene (601023).
For a general phenotypic description and a discussion of genetic
heterogeneity of amyotrophic lateral sclerosis (ALS), see ALS1 (105400).
DESCRIPTION
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease
characterized by upper and lower motor neuron dysfunction resulting in
rapidly progressive paralysis and death from respiratory failure. The
pathologic hallmarks of the disease include pallor of the corticospinal
tract due to loss of motor neurons, presence of ubiquitin-positive
inclusions within surviving motor neurons, and deposition of pathologic
TDP43 (TARDBP; 605078) aggregates. Patients with ALS14 may develop
frontotemporal dementia (FTD) (summary by Johnson et al., 2010).
See inclusion body myopathy with early-onset Paget disease and
frontotemporal dementia (IBMPFD; 167320), which is also caused by
mutation in the VCP gene and shows some overlapping features. In some
families with a VCP mutation, some family members may have ALS14, and
other members may have IBMPFD.
CLINICAL FEATURES
Johnson et al. (2010) reported an Italian family in which 4 affected
members had ALS. Affected individuals presented in adulthood (range, 37
to 53 years) with limb-onset motor neuron symptoms that rapidly
progressed to involve all 4 limbs and the bulbar musculature, consistent
with a classic ALS phenotype. All patients had unequivocal upper and
lower motor signs, and none had evidence of Paget disease. One patient
showed mild frontotemporal dementia. Autopsy material was not available.
A parent of the proband had died at age 58 with dementia, parkinsonism,
Paget disease, and upper limb weakness, suggesting IBMPFD. The findings
indicated an expanded phenotypic spectrum for VCP mutations. In another
family, 2 patients had ALS with frontotemporal dementia, and a third had
Paget disease followed by ALS, suggesting an overlap with IBMPFD.
Johnson et al. (2010) reported a patient with classic ALS confirmed by
postmortem studies, who was a member of a large family with IBMPFD
previously reported by Watts et al. (2004). However, the family member
reported by Johnson et al. (2010) had rapidly progressive ALS without
evidence of Paget disease, myopathy, or FTD. Postmortem examination of
this patient showed loss of brainstem and spinal cord motor neurons with
Bunina bodies in surviving neurons, TDP43-positive immunostaining, and
mild pallor of the lateral corticospinal tracts, all features consistent
with a diagnosis of ALS. The patient carried the same heterozygous
mutation as his family members with IBMPFD (R155H; 601023.0001),
indicating an expanded phenotype associated with this mutation.
MOLECULAR GENETICS
Using exome sequencing, Johnson et al. (2010) identified a heterozygous
mutation in the VCP gene (R191Q; 601023.0006) in 4 affected members of
an Italian family with ALS14 with or without FTD. Screening of the VCP
gene in 210 familial ALS cases and 78 autopsy-proven ALS cases
identified 3 additional pathogenic VCP mutations (601023.0001;
601023.0008, and 601023.0009) in 4 patients. The findings expanded the
phenotype associated with VCP mutations to include classic ALS.
*FIELD* RF
1. Johnson, J. O.; Mandrioli, J.; Benatar, M.; Abramzon, Y.; Van Deerlin,
V. M.; Trojanowski, J. Q.; Gibbs, J. R.; Brunetti, M.; Gronka, S.;
Wuu, J.; Ding, J.; McCluskey, L.; and 25 others: Exome sequencing
reveals VCP mutations as a cause of familial ALS. Neuron 68: 857-864,
2010. Note: Erratum: Neuron 69: 397 only, 2011.
2. Watts, G. D. J.; Wymer, J.; Kovach, M. J.; Mehta, S. G.; Mumm,
S.; Darvish, D.; Pestronk, A.; Whyte, M. P.; Kimonis, V. E.: Inclusion
body myopathy associated with Paget disease of bone and frontotemporal
dementia is caused by mutant valosin-containing protein. Nature Genet. 36:
377-381, 2004.
*FIELD* CD
Cassandra L. Kniffin: 5/4/2011
*FIELD* ED
alopez: 09/21/2011
terry: 5/19/2011
wwang: 5/18/2011
ckniffin: 5/5/2011
*RECORD*
*FIELD* NO
613954
*FIELD* TI
#613954 AMYOTROPHIC LATERAL SCLEROSIS 14, WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA;
read moreALS14
*FIELD* TX
A number sign (#) is used with this entry because amyotrophic lateral
sclerosis-14 with or without frontotemporal dementia (ALS14) is caused
by heterozygous mutation in the VCP gene (601023).
For a general phenotypic description and a discussion of genetic
heterogeneity of amyotrophic lateral sclerosis (ALS), see ALS1 (105400).
DESCRIPTION
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease
characterized by upper and lower motor neuron dysfunction resulting in
rapidly progressive paralysis and death from respiratory failure. The
pathologic hallmarks of the disease include pallor of the corticospinal
tract due to loss of motor neurons, presence of ubiquitin-positive
inclusions within surviving motor neurons, and deposition of pathologic
TDP43 (TARDBP; 605078) aggregates. Patients with ALS14 may develop
frontotemporal dementia (FTD) (summary by Johnson et al., 2010).
See inclusion body myopathy with early-onset Paget disease and
frontotemporal dementia (IBMPFD; 167320), which is also caused by
mutation in the VCP gene and shows some overlapping features. In some
families with a VCP mutation, some family members may have ALS14, and
other members may have IBMPFD.
CLINICAL FEATURES
Johnson et al. (2010) reported an Italian family in which 4 affected
members had ALS. Affected individuals presented in adulthood (range, 37
to 53 years) with limb-onset motor neuron symptoms that rapidly
progressed to involve all 4 limbs and the bulbar musculature, consistent
with a classic ALS phenotype. All patients had unequivocal upper and
lower motor signs, and none had evidence of Paget disease. One patient
showed mild frontotemporal dementia. Autopsy material was not available.
A parent of the proband had died at age 58 with dementia, parkinsonism,
Paget disease, and upper limb weakness, suggesting IBMPFD. The findings
indicated an expanded phenotypic spectrum for VCP mutations. In another
family, 2 patients had ALS with frontotemporal dementia, and a third had
Paget disease followed by ALS, suggesting an overlap with IBMPFD.
Johnson et al. (2010) reported a patient with classic ALS confirmed by
postmortem studies, who was a member of a large family with IBMPFD
previously reported by Watts et al. (2004). However, the family member
reported by Johnson et al. (2010) had rapidly progressive ALS without
evidence of Paget disease, myopathy, or FTD. Postmortem examination of
this patient showed loss of brainstem and spinal cord motor neurons with
Bunina bodies in surviving neurons, TDP43-positive immunostaining, and
mild pallor of the lateral corticospinal tracts, all features consistent
with a diagnosis of ALS. The patient carried the same heterozygous
mutation as his family members with IBMPFD (R155H; 601023.0001),
indicating an expanded phenotype associated with this mutation.
MOLECULAR GENETICS
Using exome sequencing, Johnson et al. (2010) identified a heterozygous
mutation in the VCP gene (R191Q; 601023.0006) in 4 affected members of
an Italian family with ALS14 with or without FTD. Screening of the VCP
gene in 210 familial ALS cases and 78 autopsy-proven ALS cases
identified 3 additional pathogenic VCP mutations (601023.0001;
601023.0008, and 601023.0009) in 4 patients. The findings expanded the
phenotype associated with VCP mutations to include classic ALS.
*FIELD* RF
1. Johnson, J. O.; Mandrioli, J.; Benatar, M.; Abramzon, Y.; Van Deerlin,
V. M.; Trojanowski, J. Q.; Gibbs, J. R.; Brunetti, M.; Gronka, S.;
Wuu, J.; Ding, J.; McCluskey, L.; and 25 others: Exome sequencing
reveals VCP mutations as a cause of familial ALS. Neuron 68: 857-864,
2010. Note: Erratum: Neuron 69: 397 only, 2011.
2. Watts, G. D. J.; Wymer, J.; Kovach, M. J.; Mehta, S. G.; Mumm,
S.; Darvish, D.; Pestronk, A.; Whyte, M. P.; Kimonis, V. E.: Inclusion
body myopathy associated with Paget disease of bone and frontotemporal
dementia is caused by mutant valosin-containing protein. Nature Genet. 36:
377-381, 2004.
*FIELD* CD
Cassandra L. Kniffin: 5/4/2011
*FIELD* ED
alopez: 09/21/2011
terry: 5/19/2011
wwang: 5/18/2011
ckniffin: 5/5/2011