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Rare variants in SQSTM1 and VCP genes and risk of sporadic inclusion body myositis.

Gang, Q; Bettencourt, C; Machado, PM; Brady, S; Holton, JL; Pittman, AM; Hughes, D; ... Muscle Study Group and The International IBM Genetics Consortium, .; + view all (2016) Rare variants in SQSTM1 and VCP genes and risk of sporadic inclusion body myositis. Neurobiology of Aging , 47 218.e1-218.e9. 10.1016/j.neurobiolaging.2016.07.024. Green open access

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Abstract

Genetic factors have been suggested to be involved in the pathogenesis of sporadic inclusion body myositis (sIBM). Sequestosome 1 (SQSTM1) and valosin-containing protein (VCP) are 2 key genes associated with several neurodegenerative disorders but have yet to be thoroughly investigated in sIBM. A candidate gene analysis was conducted using whole-exome sequencing data from 181 sIBM patients, and whole-transcriptome expression analysis was performed in patients with genetic variants of interest. We identified 6 rare missense variants in the SQSTM1 and VCP in 7 sIBM patients (4.0%). Two variants, the SQSTM1 p.G194R and the VCP p.R159C, were significantly overrepresented in this sIBM cohort compared with controls. Five of these variants had been previously reported in patients with degenerative diseases. The messenger RNA levels of major histocompatibility complex genes were upregulated, this elevation being more pronounced in SQSTM1 patient group. We report for the first time potentially pathogenic SQSTM1 variants and expand the spectrum of VCP variants in sIBM. These data suggest that defects in neurodegenerative pathways may confer genetic susceptibility to sIBM and reinforce the mechanistic overlap in these neurodegenerative disorders.

Type: Article
Title: Rare variants in SQSTM1 and VCP genes and risk of sporadic inclusion body myositis.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.neurobiolaging.2016.07.024
Publisher version: http://dx.doi.org/10.1016/j.neurobiolaging.2016.07...
Language: English
Additional information: © 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Genetic risk factor, SQSTM1, Sporadic inclusion body myositis, VCP, sIBM
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: http://discovery.ucl.ac.uk/id/eprint/1514790
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