Rare variants in SQSTM1 and VCP genes and risk of sporadic inclusion body myositis.
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.
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.
Qiang
Q
Gang
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.
Conceição
C
Bettencourt
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.
Pedro M
PM
Machado
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.
Stefen
S
Brady
MRC Centre for Neuromuscular Diseases, Institute of Neurology, University College London, Queen Square, London, UK.
Janice L
JL
Holton
Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London, UK; Reta Lila Weston Laboratories, UCL Institute of Neurology, London, UK.
Alan M
AM
Pittman
Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square, London, UK.
Deborah
D
Hughes
MRC Centre for Neuromuscular Diseases, Institute of Neurology, University College London, Queen Square, London, UK.
Estelle
E
Healy
MRC Centre for Neuromuscular Diseases, Institute of Neurology, University College London, Queen Square, London, UK.
Matthew
M
Parton
Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK.
David
D
Hilton-Jones
Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
Perry B
PB
Shieh
Western Australian Neurosciences Research Institute (WANRI), University of Western Australia and Murdoch University, Fiona Stanley Hospital, Perth, Australia.
Merrilee
M
Needham
Department of Neurology, Royal North Shore Hospital, New South Wales, Australia.
Christina
C
Liang
Department of Neurology, Medical School of the University of São Paulo (FMUSP), São Paulo, Brazil.
Edmar
E
Zanoteli
Department of Neurology, Medical School of the University of São Paulo (FMUSP), São Paulo, Brazil.
Leonardo Valente
LV
de Camargo
Department of Neurology and Neuromuscular Reference Centre, Ghent University Hospital, Ghent, Belgium.
Boel
B
De Paepe
Department of Neurology and Neuromuscular Reference Centre, Ghent University Hospital, Ghent, Belgium.
Jan
J
De Bleecker
Nerve and Muscle Center of Texas, Houston, TX, USA.
Aziz
A
Shaibani
Neuromuscular Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Centre, University of Milan, Milan, Italy.
Michela
M
Ripolone
Neuromuscular Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Centre, University of Milan, Milan, Italy.
Raffaella
R
Violano
Neuromuscular Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Centre, University of Milan, Milan, Italy.
Maurizio
M
Moggio
The University of Kansas Medical Centre, Kansas City, KS, USA.
Richard J
RJ
Barohn
The University of Kansas Medical Centre, Kansas City, KS, USA.
Mazen M
MM
Dimachkie
Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Isitituto Neurologico C. Besta, Milano, Italy.
Marina
M
Mora
Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Isitituto Neurologico C. Besta, Milano, Italy.
Renato
R
Mantegazza
Neuromuscular Diseases and Neuroimmunology Unit, Fondazione IRCCS Isitituto Neurologico C. Besta, Milano, Italy.
Simona
S
Zanotti
Laboratory of Neurogenetics, National Institute on Aging, National Institute of Health, Bethesda, MD, USA.
Andrew B
AB
Singleton
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.
Michael G
MG
Hanna
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.
Henry
H
Houlden
D000251:Adenosine Triphosphatases / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D018797:Cell Cycle Proteins / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D018979:Myositis, Inclusion Body / Q000235:genetics*; D012306:Risk; D000071456:Sequestosome-1 Protein / Q000235:genetics*; D000074405:Valosin Containing Protein
D018797:Cell Cycle Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein
Genetic risk factor; SQSTM1; Sporadic inclusion body myositis; VCP; sIBM