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

Neurobiology of Aging2016Vol. 47, pp. 218.e1–218.e9

Citations Over TimeTop 10% of 2016 papers

Qiang Gang, Conceição Bettencourt, Pedro Machado, Stefen Brady, Janice L. Holton, Alan Pittman, Deborah Hughes, Estelle Healy, M. Parton, David Hilton‐Jones, Perry B. Shieh, Merrilee Needham, Christina Liang, Edmar Zanoteli, Leonardo Valente de Camargo, Boél De Paepe, Jan De Bleecker, Aziz Shaibani, Michela Ripolone, Raffaella Violano, Maurizio Moggio, Richard J. Barohn, Mazen M. Dimachkie, Marina Mora, Renato Mantegazza, Simona Zanotti, Andrew Singleton, Michael G. Hanna, Henry Houlden, Michael G. Hanna, Henry Houlden, Pedro Machado, Qiang Gang, Conceição Bettencourt, Estelle Healy, M. Parton, Janice L. Holton, Stefen Brady, David Hilton‐Jones, Perry B. Shieh, Edmar Zanoteli, Leonardo Valente de Camargo, Boél De Paepe, Jan De Bleecker, Aziz Shaibani, Michela Ripolone, Raffaella Violano, Maurizio Moggio, Richard J. Barohn, Mazen M. Dimachkie, April McVey, Mamatha Pasnoor, Melanie Glenn, Omar Jawdat, Jeffrey Statland, Gabrielle Rico, Marina Mora, Renato Mantegazza, Simona Zanotti, Merrilee Needham, Frank Mastaglia, Christina Liang, Marinos C. Dalakas, Angie Biba, Hector Chinoy, James B Lilleker, Janine A. Lamb, Hazel Platt, Robert G. Cooper, James Miller, Mark Roberts, Elizabeth Househam, David A. Hilton, Aditya G. Shivane, Amy Bartlett, John T. Kissel, Heidi M. Runk, Matthew Wicklund, David Saperstein, Lynette R. McKinney

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.

Citations Over TimeTop 10% of 2016 papers

Abstract

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