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

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

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)218.e1-218.e9
JournalNeurobiology of Aging
StatePublished - Nov 1 2016
Externally publishedYes


  • Genetic risk factor
  • SQSTM1
  • Sporadic inclusion body myositis
  • VCP
  • sIBM

ASJC Scopus subject areas

  • General Neuroscience
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology


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