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; 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

doi:10.1016/j.neurobiolaging.2016.07.024

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

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45 Scopus citations

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.

Original language	English (US)
Pages (from-to)	218.e1-218.e9
Journal	Neurobiology of Aging
Volume	47
DOIs	https://doi.org/10.1016/j.neurobiolaging.2016.07.024
State	Published - Nov 1 2016
Externally published	Yes

Keywords

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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10.1016/j.neurobiolaging.2016.07.024

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Gang, Q., Bettencourt, C., Machado, P. M., Brady, S., Holton, J. L., Pittman, A. M., Hughes, D., Healy, E., Parton, M., Hilton-Jones, D., Shieh, P. B., Needham, M., Liang, C., Zanoteli, E., de Camargo, L. V., De Paepe, B., De Bleecker, J., Shaibani, A., Ripolone, M., ... McKinney, L. R. (2016). Rare variants in SQSTM1 and VCP genes and risk of sporadic inclusion body myositis. Neurobiology of Aging, 47, 218.e1-218.e9. https://doi.org/10.1016/j.neurobiolaging.2016.07.024

Gang, Q, Bettencourt, C, Machado, PM, Brady, S, Holton, JL, Pittman, AM, Hughes, D, Healy, E, Parton, M, Hilton-Jones, D, Shieh, PB, Needham, M, Liang, C, Zanoteli, E, de Camargo, LV, De Paepe, B, De Bleecker, J, Shaibani, A, Ripolone, M, Violano, R, Moggio, M, Barohn, RJ, Dimachkie, MM, Mora, M, Mantegazza, R, Zanotti, S, Singleton, AB, Hanna, MG, Houlden, H, McVey, AL, Pasnoor, M, Glenn, M, Jawdat, O, Statland, J, Rico, G, Mastaglia, F, Dalakas, MC, Biba, A, Chinoy, H, Lilleker, JB, Lamb, J, Platt, H, Cooper, RG, Miller, JAL, Roberts, M, Househam, E, Hilton, D, Shivane, A, Bartlett, A, Kissel, JT, Runk, H, Wicklund, M, Saperstein, DS & McKinney, LR 2016, 'Rare variants in SQSTM1 and VCP genes and risk of sporadic inclusion body myositis', Neurobiology of Aging, vol. 47, pp. 218.e1-218.e9. https://doi.org/10.1016/j.neurobiolaging.2016.07.024

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title = "Rare variants in SQSTM1 and VCP genes and risk of sporadic inclusion body myositis",

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",

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

note = "Publisher Copyright: {\textcopyright} 2016 The Author(s)",

year = "2016",

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doi = "10.1016/j.neurobiolaging.2016.07.024",

language = "English (US)",

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TY - JOUR

T1 - Rare variants in SQSTM1 and VCP genes and risk of sporadic inclusion body myositis

AU - Gang, Qiang

AU - Bettencourt, Conceição

AU - Machado, Pedro M.

AU - Brady, Stefen

AU - Holton, Janice L.

AU - Pittman, Alan M.

AU - Hughes, Deborah

AU - Healy, Estelle

AU - Parton, Matthew

AU - Hilton-Jones, David

AU - Shieh, Perry B.

AU - Needham, Merrilee

AU - Liang, Christina

AU - Zanoteli, Edmar

AU - de Camargo, Leonardo Valente

AU - De Paepe, Boel

AU - De Bleecker, Jan

AU - Shaibani, Aziz

AU - Ripolone, Michela

AU - Violano, Raffaella

AU - Moggio, Maurizio

AU - Barohn, Richard J.

AU - Dimachkie, Mazen M.

AU - Mora, Marina

AU - Mantegazza, Renato

AU - Zanotti, Simona

AU - Singleton, Andrew B.

AU - Hanna, Michael G.

AU - Houlden, Henry

AU - McVey, April L.

AU - Pasnoor, Mamatha

AU - Glenn, Melanie

AU - Jawdat, Omar

AU - Statland, Jeffrey

AU - Rico, Gabrielle

AU - Mastaglia, Frank

AU - Dalakas, Marinos C.

AU - Biba, Angie

AU - Chinoy, Hector

AU - Lilleker, James B.

AU - Lamb, Janine

AU - Platt, Hazel

AU - Cooper, Robert G.

AU - Miller, James A.L.

AU - Roberts, Mark

AU - Househam, Elizabeth

AU - Hilton, David

AU - Shivane, Aditya

AU - Bartlett, Amy

AU - Kissel, John T.

AU - Runk, Heidi

AU - Wicklund, Matthew

AU - Saperstein, David S.

AU - McKinney, Lynette R.

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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.

AB - 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.

KW - Genetic risk factor

KW - SQSTM1

KW - Sporadic inclusion body myositis

KW - VCP

KW - sIBM

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U2 - 10.1016/j.neurobiolaging.2016.07.024

DO - 10.1016/j.neurobiolaging.2016.07.024

M3 - Article

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AN - SCOPUS:84994512347

SN - 0197-4580

VL - 47

SP - 218.e1-218.e9

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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