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

Gang, Q., Bettencourt, C., Machado, P.M., Brady, S., Holton, J.L., Pittman, A.M., Hughes, D., Healy, E., Parton, M., Hilton-Jones, D., Shieh, P.B., Needham, M., Liang, C., Zanoteli, E., de Camargo, L.V., De Paepe, B., De Bleecker, J., Shaibani, A., Ripolone, M., Violano, R., Moggio, M., Barohn, R.J., Dimachkie, M.M., Mora, M., Mantegazza, R., Zanotti, S., Singleton, A.B., Hanna, M.G. and Houlden, H. (2016) Rare variants in SQSTM1 and VCP genes and risk of sporadic inclusion body myositis. Neurobiology of Aging, 47 . e1-e9.

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Genetic factors have been suggested to be involved in the pathogenesis of sporadic inclusion body myositis (sIBM). SQSTM1 and VCP are two 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 six rare missense variants in the SQSTM1 and VCP in seven sIBM patients (4.0%). Two variants 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 mRNA levels of MHC genes were up-regulated, 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 suggests that defects in neurodegenerative pathways may confer genetic susceptibility to sIBM and reinforce the mechanistic overlap in these neurodegenerative disorders.

Item Type: Journal Article
Murdoch Affiliation(s): School of Health Professions
Publisher: Elsevier Inc
Copyright: 2016 The Authors
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