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

Qiang Gang, Conceição Bettencourt, P. MacHado, Stefen Brady, Janice L. Holton, Alan Pittman, Deborah Hughes, Estelle Healy, M. Parton, D. Hilton-Jones, Perry B. Shieh, Merrilee Needham, Christina Liang, Edmar Zanoteli, Leonardo Valente de Camargo, Boel De Paepe, J. L. De Bleecker, Aziz Shaibani, Michela Ripolone, Raffaella ViolanoMaurizio Moggio, Richard J. Barohn, Mazen M. Dimachkie, Marina Mora, Renato Mantegazza, Simona Zanotti, Andrew Singleton, M. G. Hanna, Henry Houlden

Research output: Contribution to journalArticlepeer-review


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
JournalNeurobiology of Aging
Publication statusAccepted/In press - Mar 17 2016


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

ASJC Scopus subject areas

  • Neuroscience(all)
  • Ageing
  • Developmental Biology
  • Geriatrics and Gerontology
  • Clinical Neurology


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