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

被引：41

作者：

Gang, Qiang ^{[1
,2
]}

Bettencourt, Conceicao ^{[1
,3
]}

Machado, Pedro M. ^{[1
,2
,4
]}

Brady, Stefen ^{[2
,5
]}

Holton, Janice L. ^{[2
]}

Pittman, Alan M. ^{[1
,6
]}

Hughes, Deborah ^{[1
]}

Healy, Estelle ^{[2
]}

Parton, Matthew ^{[2
]}

Hilton-Jones, David ^{[5
]}

Shieh, Perry B. ^{[7
]}

Needham, Merrilee ^{[8
,9
]}

Liang, Christina ^{[10
]}

Zanoteli, Edmar ^{[11
]}

de Camargo, Leonardo Valente ^{[11
]}

De Paepe, Boel ^{[12
,13
]}

De Bleecker, Jan ^{[12
,13
]}

Shaibani, Aziz ^{[14
]}

Ripolone, Michela ^{[15
]}

Violano, Raffaella ^{[15
]}

Moggio, Maurizio ^{[15
]}

Barohn, Richard J. ^{[16
]}

Dimachkie, Mazen M. ^{[16
]}

Mora, Marina ^{[17
]}

Mantegazza, Renato ^{[17
]}

Zanotti, Simona ^{[17
]}

Singleton, Andrew B. ^{[18
]}

Hanna, Michael G. ^{[1
,2
]}

Houlden, Henry ^{[1
,2
,19
]}

机构：

[1] UCL, Inst Neurol, Dept Mol Neurosci, Queen Sq, London, England

[2] UCL, Inst Neurol, MRC Ctr Neuromuscular Dis, Queen Sq, London, England

[3] UCL, Inst Neurol, Dept Clin & Expt Epilepsy, Queen Sq, London, England

[4] UCL, Div Med, Ctr Rheumatol, London, England

[5] John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Oxford, England

[6] UCL Inst Neurol, Reta Lila Weston Labs, London, England

[7] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA

[8] Univ Western Australia, WANRI, Perth, WA, Australia

[9] Murdoch Univ, Fiona Stanley Hosp, Perth, WA, Australia

[10] Royal North Shore Hosp, Dept Neurol, St Leonards, NSW, Australia

[11] Univ Sao Paulo FMUSP, Sch Med, Dept Neurol, Sao Paulo, Brazil

[12] Ghent Univ Hosp, Dept Neurol, Ghent, Belgium

[13] Ghent Univ Hosp, Neuromuscular Reference Ctr, Ghent, Belgium

[14] Nerve & Muscle Ctr Texas, Houston, TX USA

[15] Univ Milan, Dino Ferrari Ctr, IRCCS Fdn Ca Granda Osped Maggiore Policlin, Neuromuscular Unit, Milan, Italy

[16] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA

[17] Fdn IRCCS Ist Neurol C Besta, Neuromuscular Dis & Neuroimmunol Unit, Milan, Italy

[18] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA

[19] UCL, Inst Neurol, Neurogenet Lab, Queen Sq, London, England

来源：

NEUROBIOLOGY OF AGING | 2016年 / 47卷

基金：

英国惠康基金;

关键词：

Sporadic inclusion body myositis; sIBM; SQSTM1; VCP; Genetic risk factor; FRONTOTEMPORAL DEMENTIA; PAGET-DISEASE; MUTATION; MYOPATHY;

D O I：

10.1016/j.neurobiolaging.2016.07.024

中图分类号：

R592 [老年病学]; C [社会科学总论];

学科分类号：

03 ; 0303 ; 100203 ;

摘要：

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. (C) 2016 The Author(s). Published by Elsevier Inc.

引用

页码：218.e1 / 218.e9

页数：9

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