Pathological consequences of VCP mutations on human striated muscle
Open accessAbstract
Mutations in the valosin-containing protein (VCP, p97) gene on chromosome 9p13-p12 cause a late-onset form of autosomal dominant inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia (IBMPFD). We report on the pathological consequences of three heterozygous VCP (R93C, R155H, R155C) mutations on human striated muscle. IBMPFD skeletal muscle pathology is characterized by degenerative changes and filamentous VCP- and ubiquitin-positive cytoplasmic and nuclear protein aggregates. Furthermore, this is the first report demonstrating that mutant VCP leads to a novel form of dilatative cardiomyopathy with inclusion bodies. In contrast to post-mitotic striated muscle cells and neurons of IBMPFD patients, evidence of protein aggregate pathology was not detected in primary IBMPFD myoblasts or in transient and stable transfected cells using wild-type-VCP and R93C-, R155H-, R155C-VCP mutants. Glutathione S-transferase pull-down experiments showed that all three VCP mutations do not affect the binding to Ufd1, Npl4 and ataxin-3. Structural analysis demonstrated that R93 and R155 are both surface-accessible residues located in the centre of cavities that may enable ligand-binding. Mutations at R93 and R155 are predicted to induce changes in the tertiary structure of the VCP protein. The search for putative ligands to the R93 and R155 cavities resulted in the identification of cyclic sugar compounds with high binding scores. The latter findings provide a novel link to VCP carbohydrate interactions in the complex pathology of IBMPFD.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Histopathological analyses consistently show TARDBP, ubiquitin and SQSTM1-positive inclusions in VCP-related diseases.
“Histopathological analyses consistently illustrate TARDBP, ubiquitin and SQSTM1-positive inclusions in VCP-related diseases [244–247].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [245]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
PROCHECK: a program to check the stereochemical quality of protein structures
Laskowski, R. A., MacArthur, M. W., Moss, D. S., & Thornton, J. M. (1993) · Journal of Applied Crystallography · doi:10.1107/s0021889892009944 · Cited by 24,581 · see citing works
Jones, T. A., Zou, J.-Y., Cowan, S. W., & Kjeldgaard, M. (1991) · Acta Crystallographica Section A Foundations of Crystallography · doi:10.1107/s0108767390010224 · Cited by 12,650 · see citing works
LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions
Wallace, A. C., Laskowski, R. A., & Thornton, J. M. (1995) · Protein Engineering Design and Selection · doi:10.1093/protein/8.2.127 · Cited by 5,705 · see citing works
Spiro, R. G. (2002) · Glycobiology · doi:10.1093/glycob/12.4.43r · Cited by 1,414 · see citing works
Watts, G. D. J., Wymer, J., Kovach, M. J., Mehta, S. G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M. P., & Kimonis, V. E. (2004) · Nature Genetics · doi:10.1038/ng1332 · Cited by 1,391 · see citing works
Self-citationScherzinger, E., Lurz, R., Turmaine, M., Mangiarini, L., Hollenbach, B., Hasenbank, R., Bates, G. P., Davies, S. W., Lehrach, H., & Wanker, E. E. (1997) · Cell · doi:10.1016/s0092-8674(00)80514-0 · Cited by 1,291 · cited 1× · see citing works
“GST-, MBP- and His-tagged fusion proteins were expressed in Escherichia coli and purified on affinity columns as described previously (Scherzinger et al., 1997) and according to manufacturer’s instructions (NEB, USA; Qiagen, Germany).”
Self-citationThe AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol
Ye, Y., Meyer, H. H., & Rapoport, T. A. (2001) · Nature · doi:10.1038/414652a · Cited by 1,099 · see citing works
A missense mutation in the αB-crystallin chaperone gene causes a desmin-related myopathy
Vicart, P., Caron, A., Guicheney, P., Li, Z., Prévost, M., Faure, A., Château, D., Chapon, F., Tomé, F. M. S., Dupret, J., et al. (1998) · Nature Genetics · doi:10.1038/1765 · Cited by 1,077 · see citing works
A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol
Ye, Y., Shibata, Y., Yun, C., Ron, D., & Rapoport, T. A. (2004) · Nature · doi:10.1038/nature02656 · Cited by 963 · see citing works
Bledsoe, R. K., Montana, V. G., Stanley, T. B., Delves, C. J., Apolito, C. J., McKee, D. D., Consler, T. G., Parks, D. J., Stewart, E. L., Willson, T. M., et al. (2002) · Cell · doi:10.1016/s0092-8674(02)00817-6 · Cited by 818 · see citing works
Crystallographic comparison of the estrogen and progesterone receptor’s ligand binding domains
Tanenbaum, D. M., Wang, Y., Williams, S. P., & Sigler, P. B. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.5998 · Cited by 742 · see citing works
Atomic structure of progesterone complexed with its receptor
Williams, S. P., & Sigler, P. B. (1998) · Nature · doi:10.1038/30775 · Cited by 659 · see citing works
Waelter, S., Boeddrich, A., Lurz, R., Scherzinger, E., Lüder, G., Lehrach, H. R., & Wanker, E. E. (2001) · Molecular Biology of the Cell · doi:10.1091/mbc.12.5.1393 · Cited by 632 · see citing works
Self-citationRabinovich, E., Kerem, A., Fröhlich, K., Diamant, N., & Bar‐Nun, S. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.2.626-634.2002 · Cited by 546 · see citing works
Meyer, H. H., Shorter, J., Seemann, J., Pappin, D., & Warren, G. (2000) · The EMBO Journal · doi:10.1093/emboj/19.10.2181 · Cited by 446 · see citing works
p47 is a cofactor for p97-mediated membrane fusion
Kondo, H., Rabouille, C., Newman, R., Levine, T. P., Pappin, D., Freemont, P. S., & Warren, G. (1997) · Nature · doi:10.1038/40411 · Cited by 437 · see citing works
DeLaBarre, B., & Brünger, A. T. (2003) · Nature Structural & Molecular Biology · doi:10.1038/nsb972 · Cited by 386 · see citing works
Lilley, B. N., & Ploegh, H. L. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0505014102 · Cited by 315 · see citing works
Distinct AAA-ATPase p97 complexes function in discrete steps of nuclear assembly
Hetzer, M. W., Meyer, H. H., Walther, T. C., Bilbao, D., Warren, G., & Mattaj, I. W. (2001) · Nature Cell Biology · doi:10.1038/ncb1201-1086 · Cited by 311 · see citing works
Proteasome Inhibitors Activate Stress Kinases and Induce Hsp72
Meriin, A. B., Gabai, V. L., Yaglom, J., Shifrin, V. I., & Sherman, M. Y. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.11.6373 · Cited by 300 · see citing works
Myofibrillar myopathy: clinical, morphological and genetic studies in 63 patients
Selcen, D. (2004) · Brain · doi:10.1093/brain/awh052 · Cited by 299 · see citing works
Hirabayashi, M., Inoue, K., Tanaka, K., Nakadate, K., Ohsawa, Y., Kamei, Y., Popiel, A. H., Shinohara, A., Iwamatsu, A., Kimura, Y., et al. (2001) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400907 · Cited by 258 · see citing works
Rabouille, C., Kondo, H., Newman, R., Hui, N., Freemont, P. S., & Warren, G. (1998) · Cell · doi:10.1016/s0092-8674(00)81128-9 · Cited by 256 · see citing works
[24] Membrane filter assay for detection of amyloid-like polyglutamine-containing protein aggregates
Wanker, E. E., Scherzinger, E., Heiser, V., Sittler, A., Eickhoff, H., & Lehrach, H. R. (1999) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(99)09026-6 · Cited by 234 · see citing works
Self-citationPlacement of medium-sized molecular fragments into active sites of proteins
Rarey, M., Wefing, S., & Lengauer, T. (1996) · Journal of Computer-Aided Molecular Design · doi:10.1007/bf00124464 · Cited by 206 · see citing works
Weihl, C. C., Dalal, S. R., Pestronk, A., & Hanson, P. I. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi426 · Cited by 195 · see citing works
Li, Y., Suino, K., Daugherty, J., & Xu, H. (2005) · Molecules and Cells · doi:10.1016/j.molcel.2005.06.026 · Cited by 188 · see citing works
Structural basis of the interaction between the AAA ATPase p97/VCP and its adaptor protein p47
Dreveny, I., Kondo, H., Uchiyama, K., Shaw, A., Zhang, X., & Freemont, P. S. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600139 · Cited by 188 · see citing works
Mutant valosin‐containing protein causes a novel type of frontotemporal dementia
Schröder, 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. (2005) · Annals of Neurology · doi:10.1002/ana.20407 · Cited by 177 · see citing works
Self-citationDiagnostic value of muscle MRI in differentiating LGMD2I from other LGMDs
Fischer, D., Walter, M. C., Kesper, K., et al. (2005) · Journal of Neurology · doi:10.1007/s00415-005-0684-4 · Cited by 158 · see citing works
Self-citationAn arginine/lysine‐rich motif is crucial for VCP/p97‐mediated modulation of ataxin‐3 fibrillogenesis
Boeddrich, A., Gaumer, S., Haacke, A., Tzvetkov, N., Albrecht, M., Evert, B. O., Müller, E. C., Lurz, R., Breuer, P., Schugardt, N., et al. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601043 · Cited by 156 · see citing works
Self-citationAtaxin-3 is transported into the nucleus and associates with the nuclear matrix
Tait, D. S. (1998) · Human Molecular Genetics · doi:10.1093/hmg/7.6.991 · Cited by 119 · see citing works
Ardley, H. C., Scott, G. B., Rose, S. A., Tan, N. G. S., Markham, A. F., & Robinson, P. A. (2003) · Molecular Biology of the Cell · doi:10.1091/mbc.e03-02-0078 · Cited by 119 · see citing works
The Cyclase-associated Protein CAP as Regulator of Cell Polarity and cAMP Signaling inDictyostelium
Noegel, A. A., Blau‐Wasser, R., Sultana, H., Müller, R., Israel, L., Schleicher, M., Patel, H., & Weijer, C. J. (2003) · Molecular Biology of the Cell · doi:10.1091/mbc.e03-05-0269 · Cited by 112 · see citing works
Self-citationInclusion body myopathy and Paget disease is linked to a novel mutation in the VCP gene
Haubenberger, D., Bittner, R. E., Shorny, S., Zimprich, F., Mannhalter, C., Wagner, L., Mineva, I., Vass, K., Auff, E., & Zimprich, A. A. (2005) · Neurology · doi:10.1212/01.wnl.0000180407.15369.92 · Cited by 108 · see citing works
Schröder, R., Kunz, W. S., Rouan, F., et al. (2002) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/61.6.520 · Cited by 108 · see citing works
A window of opportunity: timing protein degradation by trimming of sugars and ubiquitins.
Lederkremer, G., & Glickman, M. (2005) · TIBS -Trends in Biochemical Sciences. Regular ed · doi:10.1016/j.tibs.2005.04.010 · Cited by 106 · see citing works
Schröder, R., Goudeau, B., Simon, M. C., et al. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg060 · Cited by 105 · see citing works
D’Alessandro, M., Russell, D., Morley, S. M., Davies, A. M., & Lane, E. B. (2002) · Journal of Cell Science · doi:10.1242/jcs.00120 · Cited by 105 · see citing works
Discovery of a Novel Family of CDK Inhibitors with the Program LIDAEUS
Wu, S. Y., McNae, I. W., Kontopidis, G. A., McClue, S. J., McInnes, C., Stewart, K., Wang, S., Zheleva, D. I., Marriage, H., Lane, D. P., et al. (2003) · Structure · doi:10.1016/s0969-2126(03)00060-1 · Cited by 105 · see citing works
Vacuole-creating protein in neurodegenerative diseases in humans
Mizuno, Y., Hori, S., Kakizuka, A., & Okamoto, K. (2003) · Neuroscience Letters · doi:10.1016/s0304-3940(03)00280-5 · Cited by 93 · see citing works
Bär, H., Fischer, D., Goudeau, B., Kley, R. A., Clemen, C. S., Vicart, P., Herrmann, H. O., Vorgerd, M., & Schröder, R. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi136 · Cited by 89 · see citing works
Self-citationGlycoprotein‐specific ubiquitin ligases recognize N‐glycans in unfolded substrates
Yoshida, Y., Adachi, E., Fukiya, K., Iwaï, K., & Tanaka, K. (2005) · EMBO Reports · doi:10.1038/sj.embor.7400351 · Cited by 81 · see citing works
Ultraviolet Radiation Induces Phosphorylation and Ubiquitin-Mediated Degradation of ΔNP63α
Westfall, M. D., Joyner, A. S., Barbieri, C. E., Livingstone, M., & Pietenpol, J. A. (2005) · Cell Cycle · doi:10.4161/cc.4.5.1685 · Cited by 74 · see citing works
Steinhilb, M. L., Turner, R. S., & Gaut, J. R. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008793200 · Cited by 69 · see citing works
Expression and localisation of annexin VII (synexin) isoforms in differentiating myoblasts.
Clemen, C. S., Hofmann, A., Zamparelli, C., & Noegel, A. A. (1999) · Journal of Muscle Research and Cell Motility · doi:10.1023/a:1005524623337 · Cited by 47 · see citing works
Self-citationRNA interference of VCP/p97 increases Mallory body formation
Nan, L., Wu, Y., Bardag‐Gorce, F., Li, J., French, B. A., Wilson, L. T., Nguyen, S. K., & French, S. W. (2004) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2004.08.006 · Cited by 33 · see citing works
Clemen, C. S., Fischer, D., Roth, U., Simon, S., Vicart, P., Kato, K., Kamińska, A., Vorgerd, M., Goldfarb, L. G., Eymard, B., et al. (2005) · FEBS Letters · doi:10.1016/j.febslet.2005.05.051 · Cited by 28 · see citing works
Self-citationDominant‐negative effect of mutant valosin‐containing protein in aggresome formation
北見真喜子, Kitami, T., Nagahama, M., et al. (2005) · FEBS Letters · doi:10.1016/j.febslet.2005.12.044 · Cited by 26 · see citing works
Flagged first, then by citations
Research works printed but not linked: 4
- Nicholls A, Bharadwaj R, Honig B. GRASP: graphical representation and analysis of surface properties. Biophys J 1993; 64: A166.
- Wanker EE, Scherzinger E, Heiser V, Sittler A, Eickhoff H, Lehrach H. Membrane filter assay for detection of amyloid-like polyglutaminecontaining protein aggregates. Methods Enzymol 1999; 309: 375-86.
- Weihl CC, Dalal S, Pestronk A, Hanson PI. Inclusion body myopathyassociated mutations in p97/VCP impair endoplasmic reticulumassociated degradation. Hum Mol Genet 2006; 15: 189-99.
- DeltaNp63alpha. Cell Cycle 2005; 4: 710-6.
Cited by
Sorted by citations
Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease
Ju, J.-S., Fuentealba, R. A., Miller, S. E., Jackson, E., Piwnica-Worms, D., Baloh, R. H., & Weihl, C. C. (2009) · Journal of Cell Biology · doi:10.1083/jcb.200908115 · Cited by 494 · see citing works
Autophagy and ALS: mechanistic insights and therapeutic implications
Chua, J. P., De Calbiac, H., Kabashi, E., & Barmada, S. J. (2022) · Autophagy · doi:10.1080/15548627.2021.1926656 · Cited by 189 · see citing works
The p97/VCP ATPase is critical in muscle atrophy and the accelerated degradation of muscle proteins
Piccirillo, R., & Goldberg, A. L. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.178 · Cited by 85 · see citing works
Nalbandian, A., Llewellyn, K. J., Kitazawa, M., Yin, H. Z., Badadani, M., Khanlou, N., Edwards, R., Nguyen, C., Mukherjee, J., Mozaffar, T., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046308 · Cited by 68 · see citing works
Self-citationKustermann, M., Manta, L., Paone, C., Kustermann, J., Lausser, L., Wiesner, C., Eichinger, L., Clemen, C. S., Schröder, R., Kestler, H. A., et al. (2018) · Autophagy · doi:10.1080/15548627.2018.1491491 · Cited by 45 · see citing works
Self-citationExercise Training Reverses Skeletal Muscle Atrophy in an Experimental Model of VCP Disease
Nalbandian, A., Nguyen, C., Katheria, V., Llewellyn, K. J., Badadani, M., Caiozzo, V., & Kimonis, V. E. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076187 · Cited by 30 · see citing works
Self-citation
- Authors
- Hubbers, C. U., Clemen, C. S., Kesper, K., Boddrich, A., Hofmann, A., Kamarainen, O., Tolksdorf, K., Stumpf, M., Reichelt, J., Roth, U., Krause, S., Watts, G., Kimonis, V., Wattjes, M. P., Reimann, J., Thal, D. R., Biermann, K., Evert, B. O., Lochmuller, H., Wanker, E. E., Schoser, B. G. H., Noegel, A. A., & Schroder, R.
- Affiliations
- University of Cologne (DE)
- University Hospital Bonn (DE)
- Institute of Structural and Molecular Biology (GB)
- Ludwig-Maximilians-Universität München (DE)
- Boston Children's Hospital (US)
- Max Delbrück Center (DE)
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-02-01
- Volume
- 130
- Issue
- 2
- Pages
- 381-393
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2162017609
- Cited by
- 170
- References
- 49
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 3 · 2023: 6 · 2022: 5 · 2021: 8 · 2020: 8 · 2019: 3 · 2018: 7 · 2017: 5 · 2016: 12 · 2015: 3 · 2014: 9 · 2013: 9 · 2012: 15
- FWCI
- 4.89
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Griffith Research Online (submittedVersion, cc-by)
- UEA Digital Repository (University of East Anglia) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Bundesministerium für Bildung und Forschung (01GM0302)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- VCP, VCP mutations, dilated cardiomyopathy, protein aggregates, ubiquitin, myoblasts, Ufd1, Npl4, ataxin-3, ligand binding, protein structure
- MeSH terms
- Valosin Containing Protein, Adenosine Triphosphatases, Aged, Cardiomyopathy, Dilated, Cells, Cultured, Chromosomes, Human, Pair 9, DNA Mutational Analysis, Female, Humans, Ligands, Male, Middle Aged, Mutation, Osteitis Deformans, Phenotype, Protein Binding, Spinal Diseases, Transduction, Genetic, Transfection, Protein Structure, Tertiary, Muscle, Skeletal, Microscopy, Confocal, Cell Cycle Proteins, Myositis, Inclusion Body, Databases, Genetic, Myoblasts
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
