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SQSTM1 and VCP mutations in a series of 205 inclusion body myositis cases

Gang, Q., Bettencourt, C., 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 Carmargo, L.V., De Paepe, B., De Bleecker, J., Shaibani, A., Ripolone, M., Violano, R., Moggio, M., Barohn, R.J., Dimachkie, M.M., Mora, M., Mantegazza, R., Zanotti, S., Singleton, A.B., Hanna, M.G., Houlden, H. and Machado, P.M. (2015) SQSTM1 and VCP mutations in a series of 205 inclusion body myositis cases. In: Muscle Study Group Meeting on Experimental Therapeutics Across the Spectrum of Neuromuscular Disease, 19 - 21 September 2015, Snowbird, UT, USA

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Introduction: Clinico-pathologically overlapping inherited dis- orders indicate that genetic factors might be involved in sporadic inclusion body myositis (IBM) pathogenesis. Objectives: To identify genetic risk factors associated with IBM.

Methods: Whole-exome sequencing was performed in 205 IBM patients. Muscle tissue was pathologically evaluated and whole- transcriptome expression profiles generated.

Results: We identified eight rare missense mutations in the SQSTM1 and VCP genes in 10 IBM patients (5%). Five of the mutations had been previously reported in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) with Paget’s disease of bone (PDB); p62 staining was increased and MHC-I was up-regulated in the muscle tissue of these patients,

Conclusions: Variants in SQSTM1 and VCP may constitute genetic susceptibility factors for IBM. The occurrence of mutations in SQSTM1 and VCP in IBM, ALS, FTD and PDB rein- forces the link between these disorders, pinpointing converging pathogenic pathways resulting in impaired autophagy-lysosome processing, causing dysregulation of protein homeostasis.

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