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Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation

De Ridder, Willem and Azmi, Abdelkrim and Clemen, Christoph S. and Eichinger, Ludwig and Hofmann, Andreas and Schröder, Rolf and Johnson, Katherine and Töpf, Ana and Straub, Volker and De Jonghe, Peter and Maudsley, Stuart and De Bleecker, Jan L. and Baets, Jonathan (2020) Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation. Neurology, 94 (8), e785-e796. Lippincott Williams & Wilkins Ltd.. doi: 10.1212/WNL.0000000000008763. ISSN 0028-3878.

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Official URL: https://n.neurology.org/content/94/8/e785


Objective: To assess the clinical, radiologic, myopathologic, and proteomic findings in a patient manifesting a multisystem proteinopathy due to a homozygous valosin-containing protein gene (VCP) mutation previously reported to be pathogenic in the heterozygous state. Methods: We studied a 36-year-old male index patient and his father, both presenting with progressive limb-girdle weakness. Muscle involvement was assessed by MRI and muscle biopsies. We performed whole-exome sequencing and Sanger sequencing for segregation analysis of the identified p.Arg159His VCP mutation. To dissect biological disease signatures, we applied state-of-the-art quantitative proteomics on muscle tissue of the index case, his father, 3 additional patients with VCP-related myopathy, and 3 control individuals. Results: The index patient, homozygous for the known p.Arg159His mutation in VCP, manifested a typical VCP-related myopathy phenotype, although with a markedly high creatine kinase value and a relatively early disease onset, and Paget disease of bone. The father exhibited a myopathy phenotype and discrete parkinsonism, and multiple deceased family members on the maternal side of the pedigree displayed a dementia, parkinsonism, or myopathy phenotype. Bioinformatic analysis of quantitative proteomic data revealed the degenerative nature of the disease, with evidence suggesting selective failure of muscle regeneration and stress granule dyshomeostasis. Conclusion: We report a patient showing a multisystem proteinopathy due to a homozygous VCP mutation. The patient manifests a severe phenotype, yet fundamental disease characteristics are preserved. Proteomic findings provide further insights into VCP-related pathomechanisms.

Item URL in elib:https://elib.dlr.de/140141/
Document Type:Article
Title:Multisystem proteinopathy due to a homozygous p.Arg159His VCP mutation
AuthorsInstitution or Email of AuthorsAuthor's ORCID iDORCID Put Code
De Ridder, WillemLaboratory of Neuromuscular PathologyUNSPECIFIEDUNSPECIFIED
Azmi, AbdelkrimInstitute Born-Bunge, Neuromics Support FacilityUNSPECIFIEDUNSPECIFIED
Clemen, Christoph S.Institute of Aerospace Medicine, German Aerospace Center (DLR), 51147 Cologne, Germanyhttps://orcid.org/0000-0002-1291-4219UNSPECIFIED
Eichinger, LudwigCentre for Biochemistry, Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germanyhttps://orcid.org/0000-0003-1594-6117UNSPECIFIED
Hofmann, AndreasInstitute of Vegetative ¨ Physiology, Medical Faculty, University of Cologne, Germany; Griffith Institute for Drug DiscoveryUNSPECIFIEDUNSPECIFIED
Schröder, RolfInstitute of Neuropathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, GermanyUNSPECIFIEDUNSPECIFIED
Johnson, KatherineBear Fight Institute, Winthrop, WA, USAUNSPECIFIEDUNSPECIFIED
Töpf, AnaMelbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia; John Walton Muscular Dystrophy Research CentreUNSPECIFIEDUNSPECIFIED
Straub, VolkerMelbourne Veterinary School, Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, Victoria, Australia; John Walton Muscular Dystrophy Research CentreUNSPECIFIEDUNSPECIFIED
De Jonghe, PeterLaboratory of Neuromuscular PathologyUNSPECIFIEDUNSPECIFIED
Maudsley, StuartVIBUAntwerp Center for Molecular Neurology, and Receptor Biology LabUNSPECIFIEDUNSPECIFIED
De Bleecker, Jan L.Institute of Genetic Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle-Upon-Tyne, UK; and Laboratory for NeuropathologyUNSPECIFIEDUNSPECIFIED
Baets, JonathanDepartment of Biomedical Sciences, University of Antwerp; Neuromuscular Reference CentreUNSPECIFIEDUNSPECIFIED
Date:25 February 2020
Journal or Publication Title:Neurology
Refereed publication:Yes
Open Access:No
Gold Open Access:No
In ISI Web of Science:Yes
Page Range:e785-e796
Publisher:Lippincott Williams & Wilkins Ltd.
Keywords:proteinopathy, homozygous, VCP mutation
HGF - Research field:Aeronautics, Space and Transport
HGF - Program:Space
HGF - Program Themes:Research under Space Conditions
DLR - Research area:Raumfahrt
DLR - Program:R FR - Research under Space Conditions
DLR - Research theme (Project):R - Vorhaben Systemphysiologie (old)
Location: Köln-Porz
Institutes and Institutions:Institute of Aerospace Medicine > Muscle and Bone Metabolism
Deposited By: Arndt, Carina
Deposited On:11 Jan 2021 12:14
Last Modified:12 Jan 2021 12:58

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