Clemen, Christoph S., Winter, Lilli ORCID: 0000-0002-6368-1160, Strucksberg, Karl-Heinz, Berwanger, Carolin, Tuerk, Matthias, Kornblum, Cornelia, Florin, Alexandra, Aguilar-Pimentel, Juan Antonio, Amarie, Oana Veronica, Becker, Lore ORCID: 0000-0002-6890-4984, Garrett, Lillian ORCID: 0000-0003-4880-7076, Hans, Wolfgang, Moreth, Kristin, Neff, Frauke, Pingen, Laura, Rathkolb, Birgit, Racz, Ildika, Rozman, Jan ORCID: 0000-0002-8035-8904, Treise, Irina, Fuchs, Helmut, Gailus-Durner, Valerie, de Angelis, Martin Hrabe ORCID: 0000-0002-7898-2353, Vorgerd, Matthias, Eichinger, Ludwig ORCID: 0000-0003-1594-6117 and Schroeder, Rolf (2018). The heterozygous R155C VCP mutation: Toxic in humans! Harmless in mice? Biochem. Biophys. Res. Commun., 503 (4). S. 2770 - 2778. SAN DIEGO: ACADEMIC PRESS INC ELSEVIER SCIENCE. ISSN 1090-2104

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Abstract

Heterozygous missense mutations in the human VCP gene cause inclusion body myopathy associated with Paget disease of bone and fronto-temporal dementia (IBMPFD) and amyotrophic lateral sclerosis (ALS). The exact molecular mechanisms by which VCP mutations cause disease manifestation in different tissues are incompletely understood. In the present study, we report the comprehensive analysis of a newly generated R155C VCP knock-in mouse model, which expresses the ortholog of the second most frequently occurring human pathogenic VCP mutation. Heterozygous R155C VCP knock-in mice showed decreased plasma lactate, serum albumin and total protein concentrations, platelet numbers, and liver to body weight ratios, and increased oxygen consumption and CD8+/Ly6C + T-cell fractions, but none of the typical human IBMPFD or ALS pathologies. Breeding of heterozygous mice did not yield in the generation of homozygous R155C VCP knock-in animals. Immunoblotting showed identical total VCP protein levels in human IBMPFD and murine R155C VCP knock-in tissues as compared to wild-type controls. However, while in human IBMPFD skeletal muscle tissue 70% of the total VCP mRNA was derived from the mutant allele, in R155C VCP knock-in mice only 5% and 7% mutant mRNA were detected in skeletal muscle and brain tissue, respectively. The lack of any obvious IBMPFD or ALS pathology could thus be a consequence of the very low expression of mutant VCP. We conclude that the increased and decreased fractions of the R155C mutant VCP mRNA in man and mice, respectively, are due to missense mutation-induced, divergent alterations in the biological half-life of the human and murine mutant mRNAs. Furthermore, our work suggests that therapy approaches lowering the expression of the mutant VCP mRNA below a critical threshold may ameliorate the intrinsic disease pathology. (C) 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Clemen, Christoph S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Winter, LilliUNSPECIFIEDorcid.org/0000-0002-6368-1160UNSPECIFIED
Strucksberg, Karl-HeinzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Berwanger, CarolinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tuerk, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kornblum, CorneliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Florin, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aguilar-Pimentel, Juan AntonioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Amarie, Oana VeronicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, LoreUNSPECIFIEDorcid.org/0000-0002-6890-4984UNSPECIFIED
Garrett, LillianUNSPECIFIEDorcid.org/0000-0003-4880-7076UNSPECIFIED
Hans, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moreth, KristinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neff, FraukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pingen, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rathkolb, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Racz, IldikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rozman, JanUNSPECIFIEDorcid.org/0000-0002-8035-8904UNSPECIFIED
Treise, IrinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fuchs, HelmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gailus-Durner, ValerieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Angelis, Martin HrabeUNSPECIFIEDorcid.org/0000-0002-7898-2353UNSPECIFIED
Vorgerd, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eichinger, LudwigUNSPECIFIEDorcid.org/0000-0003-1594-6117UNSPECIFIED
Schroeder, RolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-172688
DOI: 10.1016/j.bbrc.2018.08.038
Journal or Publication Title: Biochem. Biophys. Res. Commun.
Volume: 503
Number: 4
Page Range: S. 2770 - 2778
Date: 2018
Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE
Place of Publication: SAN DIEGO
ISSN: 1090-2104
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
AAA-ATPASE; CONFORMATIONAL-CHANGES; SKELETAL-MUSCLE; PAGET-DISEASE; MUTANT DESMIN; PROTEIN; P97; PLATFORM; BINDING; BONEMultiple languages
Biochemistry & Molecular Biology; BiophysicsMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17268

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