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Title: Rare variants in SQSTM1 and VCP genes and risk of sporadic inclusion body myositis
Authors: GANG, QiangBETTENCOURT, ConceicaoMACHADO, Pedro M.BRADY, StefenHOLTON, Janice L.PITTMAN, Alan M.HUGHES, DeborahHEALY, EstellePARTON, MatthewHILTON-JONES, DavidSHIEH, Perry B.NEEDHAM, MerrileeLIANG, ChristinaZANOTELI, EdmarCAMARGO, Leonardo Valente dePAEPE, Boel DeBLEECKER, Jan DeSHAIBANI, AzizRIPOLONE, MichelaVIOLANO, RaffaellaMOGGIO, MaurizioBAROHN, Richard J.DIMACHKIE, Mazen M.MORA, MarinaMANTEGAZZA, RenatoZANOTTI, SimonaSINGLETON, Andrew B.HANNA, Michael G.HOULDEN, Henry
Citation: NEUROBIOLOGY OF AGING, v.47, article ID 218.e1, 9p, 2016
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. (C) 2016 The Author(s).
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Artigos e Materiais de Revistas Científicas - FM/MNE
Departamento de Neurologia - FM/MNE

Artigos e Materiais de Revistas Científicas - HC/ICHC
Instituto Central - HC/ICHC

Artigos e Materiais de Revistas Científicas - LIM/15
LIM/15 - Laboratório de Investigação em Neurologia

Artigos e Materiais de Revistas Científicas - LIM/45
LIM/45 - Laboratório de Fisiopatologia Neurocirúrgica

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