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Pathological consequences of VCP mutations on human striated muscle

Item Type:Article
Title:Pathological consequences of VCP mutations on human striated muscle
Creators Name:Huebbers, C.U. and Clemen, C.S. and Kesper, K. and Boeddrich, A. and Hofmann, A. and Kaemaeraeinen, O. and Tolksdorf, K. and Stumpf, M. and Reichelt, J. and Roth, U. and Krause, S. and Watts, G. and Kimonis, V. and Wattjes, M.P. and Reimann, J. and Thal, D.R. and Biermann, K. and Evert, B.O. and Lochmueller, H. and Wanker, E.E. and Schoser, B.G. and Noegel, A.A. and Schroeder, R.
Abstract: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.
Keywords:VCP, p97, Myopathy, Cardiomyopathy, IBMPFD
Publisher:Oxford University Press
Page Range:381-393
Date:1 February 2007
Official Publication:https://doi.org/10.1093/brain/awl238
PubMed:View item in PubMed

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