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Lookup NU author(s): Dr Marianela Schiava
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. Objectives: Multisystem proteinopathy-1 (MSP1) is a late onset disease with >50 pathogenic variants in p97/VCP. MSP1 patients have multiple phenotypes that include inclusion body myopathy, Paget disease of the bone, amyotrophic lateral sclerosis, and frontotemporal dementia. There have been no clear genotype-phenotype correlations. We sought to identify genotype-phenotype correlations and associate these with VCP intrinsic ATPase activity. Methods: Patients with MSP1 were identified from the literature and the Cure VCP patient registry. Age at onset and at loss of ambulation were collated. VCP intrinsic ATPase activity was evaluated from recombinant purified protein. Results: Among the 5 most common pathogenic VCP variants in MSP1 patients, R155C patients had the earliest average age at onset (38.15 ± 9.78). This correlated with higher ATPase activity. Evaluation of 5 variants confirmed an inverse correlation between age at onset and ATPase activity (r = −0.94, p = 0.01). Discussion: Previous studies have reported that VCP pathogenic variants are “hyperactive.” Whether this elevation in VCP ATPase activity is relevant to disease is unclear. Our study supports that in vitro VCP activity correlates with disease onset and may guide the prognosis of patients with rare or unreported variants. Moreover, it suggests that inhibition of VCP ATPase activity in MSP1 may be therapeutic.
Author(s): Robinson SE, Findlay AR, Li S, Wang F, Schiava M, Daw J, Diaz-Manera J, Chou T-F, Weihl CC
Publication type: Article
Publication status: Published
Journal: Neurology: Genetics
Year: 2024
Volume: 10
Issue: 5
Print publication date: 01/10/2024
Online publication date: 12/09/2024
Acceptance date: 26/07/2024
Date deposited: 02/10/2024
ISSN (electronic): 2376-7839
Publisher: Lippincott Williams and Wilkins
URL: https://doi.org/10.1212/NXG.0000000000200191
DOI: 10.1212/NXG.0000000000200191
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