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.

Association study reveals novel risk loci for sporadic inclusion body myositis

“…Whole exome sequencing data of 30 Finnish sIBM patients did not reveal any putative causative variants in 180 known myopathy genes including SQSTM1 and VCP (more than 99% bases covered 10× or above). The previously reported SNPs in SQSTM1 (rs104893941, rs147810437, rs11548633 and rs373585056) and in VCP (rs140913250 and rs387906789) were not found in our cohort of 30 sIBM patients. No other rare variants were found in these two genes.…”

Proteomics of rimmed vacuoles define new risk allele in inclusion body myositis

“…Moreover, rare missense pathogenic variants in both VCP and SQSTM1 have been found in patients with sIBM. 14,53 …”

“…Moreover, rare missense pathogenic variants in both VCP and SQSTM1 have been found in patients with sIBM. 14,53 The pathogenesis of sIBM is uncertain and likely due to multiple contributing factors. Specifically, a combination of environmental, genetic, and age risk factors needs to be present for disease manifestation.…”

New Developments in the Genetics of Inclusion Body Myositis

“…The two rare variants identified in VCP were previously reported as putative disease-associated variants [31,42,43], and expression of these variants in cell culture causes an accumulation of the autophagosome markers p62 and LC3-II, suggestive of a disruption in autophagy [44]. Similarly, other candidate-based whole exome sequencing (WES) approaches have also identified rare VCP variants in IBM in addition to SQSTM1 [45] and ZASP [46]. The majority of these variants are in evolutionarily conserved regions, suggesting that they may have functional consequences and increase risk for disease.…”