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

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

Q. Gang, C. Bettencourt, S. Brady, J.L. Holton, A.M. Pittman, D. Hughes, E. Healy, M. Parton, D. Hilton-Jones, P.B. Shieh, …
Muscle Study Group Meeting on Experimental Therapeutics Across the Spectrum of Neuromuscular Disease (Snowbird, UT, USA, 19/09/2015–21/09/2015)
2015
DOI: https://doi.org/10.1002/mus.24792
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Abstract

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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