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 Violano; Maurizio Moggio; Richard J Barohn; Mazen M Dimachkie; Marina Mora; Renato Mantegazza; Simona Zanotti; Andrew B Singleton; Michael G Hanna; Henry Houlden; Muscle Study Group and The International IBM Genetics Consortium

doi:10.1016/j.neurobiolaging.2016.07.024

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

Neurobiol Aging. 2016 Nov:47:218.e1-218.e9. doi: 10.1016/j.neurobiolaging.2016.07.024. Epub 2016 Aug 8.

Authors

Qiang Gang¹, Conceição Bettencourt², Pedro M Machado³, Stefen Brady⁴, Janice L Holton⁵, Alan M Pittman⁶, Deborah Hughes⁷, Estelle Healy⁵, Matthew Parton⁵, David Hilton-Jones⁸, Perry B Shieh⁹, Merrilee Needham¹⁰, Christina Liang¹¹, Edmar Zanoteli¹², Leonardo Valente de Camargo¹², Boel De Paepe¹³, Jan De Bleecker¹³, Aziz Shaibani¹⁴, Michela Ripolone¹⁵, Raffaella Violano¹⁵, Maurizio Moggio¹⁵, Richard J Barohn¹⁶, Mazen M Dimachkie¹⁶, Marina Mora¹⁷, Renato Mantegazza¹⁷, Simona Zanotti¹⁷, Andrew B Singleton¹⁸, Michael G Hanna¹⁹, Henry Houlden²⁰; Muscle Study Group and The International IBM Genetics Consortium

Collaborators

Muscle Study Group and The International IBM Genetics Consortium:
Michael G Hanna, Henry Houlden, Pedro M Machado, Qiang Gang, Conceicao Bettencourt, Estelle Healy, Matthew Parton, Janice L Holton, Stefen Brady, David Hilton-Jones, Perry B Shieh, Edmar Zanoteli, Leonardo Valente de Camargo, Boel De Paepe, Jan De Bleecker, Aziz Shaibani, Michela Ripolone, Raffaella Violano, Maurizio Moggio, Richard J Barohn, Mazen M Dimachkie, April L 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 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

Affiliations

¹ Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London, UK; MRC Centre for Neuromuscular Diseases, Institute of Neurology, University College London, Queen Square, London, UK.
² Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London, UK; Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London, UK.
³ Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London, UK; MRC Centre for Neuromuscular Diseases, Institute of Neurology, University College London, Queen Square, London, UK; Centre for Rheumatology, Division of Medicine, University College London, London, UK.
⁴ MRC Centre for Neuromuscular Diseases, Institute of Neurology, University College London, Queen Square, London, UK; Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK.
⁵ MRC Centre for Neuromuscular Diseases, Institute of Neurology, University College London, Queen Square, London, UK.
⁶ Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London, UK; Reta Lila Weston Laboratories, UCL Institute of Neurology, London, UK.
⁷ Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London, UK.
⁸ Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK.
⁹ Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁰ Western Australian Neurosciences Research Institute (WANRI), University of Western Australia and Murdoch University, Fiona Stanley Hospital, Perth, Australia.
¹¹ Department of Neurology, Royal North Shore Hospital, New South Wales, Australia.
¹² Department of Neurology, Medical School of the University of São Paulo (FMUSP), São Paulo, Brazil.
¹³ Department of Neurology and Neuromuscular Reference Centre, Ghent University Hospital, Ghent, Belgium.
¹⁴ Nerve and Muscle Center of Texas, Houston, TX, USA.
¹⁵ Neuromuscular Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Centre, University of Milan, Milan, Italy.
¹⁶ The University of Kansas Medical Centre, Kansas City, KS, USA.
¹⁷ Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Isitituto Neurologico C. Besta, Milano, Italy.
¹⁸ Laboratory of Neurogenetics, National Institute on Aging, National Institute of Health, Bethesda, MD, USA.
¹⁹ Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London, UK; MRC Centre for Neuromuscular Diseases, Institute of Neurology, University College London, Queen Square, London, UK. Electronic address: m.hanna@ucl.ac.uk.
²⁰ Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London, UK; MRC Centre for Neuromuscular Diseases, Institute of Neurology, University College London, Queen Square, London, UK; Neurogenetics Laboratory, Institute of Neurology, University College London, Queen Square, London, UK. Electronic address: h.houlden@ucl.ac.uk.

PMID: 27594680
PMCID: PMC5082791
DOI: 10.1016/j.neurobiolaging.2016.07.024

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.

Keywords: Genetic risk factor; SQSTM1; Sporadic inclusion body myositis; VCP; sIBM.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphatases / genetics*
Aged
Aged, 80 and over
Cell Cycle Proteins / genetics*
Genetic Association Studies*
Genetic Predisposition to Disease
Genetic Variation / genetics*
Humans
Middle Aged
Myositis, Inclusion Body / genetics*
Risk
Sequestosome-1 Protein / genetics*
Valosin Containing Protein

Substances

Cell Cycle Proteins
SQSTM1 protein, human
Sequestosome-1 Protein
Adenosine Triphosphatases
VCP protein, human
Valosin Containing Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding