New Developments in the Genetics of Inclusion Body Myositis

Britson, Kyla A.; Yang, Stephanie; Lloyd, Thomas E.

doi:10.1007/s11926-018-0738-0

Cited by 18 publications

(12 citation statements)

References 77 publications

(69 reference statements)

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“…It was also noted that multiple alleles of HLA are enriched in most GO terms, suggesting that HLA molecules play a crucial role in the pathogenesis of IBM. This finding is consistent with previous studies stipulating that the HLA locus is the strongest risk allele in the development of IBM 10 . HLA alleles are known to be associated with a variety of autoimmune diseases, such as systemic lupus erythematosus (SLE), 11 type 1 diabetes mellitus 12 and rheumatoid arthritis(RA) 13 .…”

Section: Discussionsupporting

confidence: 92%

Bioinformatics analysis of gene expression profiles of Inclusion body myositis

2020

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Inclusion body myositis (IBM) is a disease with a poor prognosis and limited treatment options. This study aimed at exploring gene expression profile alterations, investigating the underlying mechanisms and identifying novel targets for IBM. We analysed two microarray datasets (GSE39454 and GSE128470) derived from the Gene Expression Omnibus (GEO) database. The GEO2R tool was used to screen out differentially expressed genes (DEGs) between IBM and normal samples. Gene Ontology(GO)function and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were performed using the Database for Annotation, Visualization and Integrated Discovery to identify the pathways and functional annotation of DEGs. Finally, protein-protein interaction (PPI) networks were constructed using STRING and Cytoscape, in order to identify hub genes. A total of 144 upregulated DEGs and one downregulated DEG were iden-

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Section: Discussionsupporting

confidence: 92%

Bioinformatics analysis of gene expression profiles of Inclusion body myositis

2020

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“…A common feature of these conditions may also be attributed to genetic or epigenetic associations within shared variants of the human leukocyte antigen (HLA) locus (12). In addition, sequencing of DNA from sIBM patients has interestingly identified rare missense variants in proteins regulating protein processing, such as sequestosome 1 (SQSTM1/p62) and valosin containing protein (VCP/p97) (34), the latter a previously reported autoantibody target in primary biliary cholangitis (35). It is also possible that the differentiation of the anti-NT5c1A B cell response is reflected in specific epitopes bound by autoantibodies from different diseases.…”

Section: Discussionmentioning

confidence: 99%

Anti-NT5c1A Autoantibodies as Biomarkers in Inclusion Body Myositis

et al. 2019

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Objective: Sporadic Inclusion Body Myositis (sIBM) is an inflammatory myopathy (IIM) without a specific diagnostic biomarker until autoantibodies to the cytosolic 5′-nucleotidase 1A ( NT5c1A /Mup44) were reported. The objectives of our study were to determine the sensitivity and specificity of anti-NT5c1A for sIBM, demonstrate demographic, clinical and serological predictors for anti-NT5c1A positivity and determine if anti-nuclear antibody (ANA) indirect immunofluorescence (IIF) staining on HEp-2 cells is a reliable screening method for anti-NT5c1A. Methods: Sera from sIBM patients and controls were stored at −80°C until required for analysis. IgG antibodies to NT5c1A were detected by an addressable laser bead immunoassay (ALBIA) using a full-length human recombinant protein. Autoantibodies to other autoimmune myopathy antigens (Jo-1, OJ, TIF1y, PL-12, SAE, EJ, MDA5, PL7, SRP, NXP2, MI-2) were detected by line immunoassay (LIA), chemiluminescence immunoassay (CIA) or enzyme linked immunosorbent assay (ELISA) and ANA detected by IIF on HEp-2 substrate. Demographic, clinical and serological data were obtained by chart review. Results: Forty-three patients with sIBM, 537 disease control patients with other autoimmune, degenerative and neuromuscular diseases, and 78 healthy controls were included. 48.8% (21/43) of sIBM patients were positive for anti-NT5c1A. The overall sensitivity, specificity, positive predictive value, and negative predictive value of anti-NT5c1A for sIBM were 0.49, 0.92, 0.29, and 0.96, respectively. Compared to sIBM, the frequency of anti-NT5c1A was lower in both the disease control group (8.8%, OR 0.10 [95%CI: 0.05–0.20], p < 0.0001) and in the apparently healthy control group (5.1%, OR 0.06 [95%CI: 0.02–0.18], p < 0.0001). In the univariable analysis, sIBM patients with more severe muscle weakness were more likely to be anti-NT5c1A positive (OR 4.10 [95% CI: 1.17, 14.33], p = 0.027), although this was not statistically significant (adjusted OR 4.30 [95% CI: 0.89, 20.76], p = 0.069) in the multivariable analysis. The ANA of sIBM sera did not demonstrate a consistent IIF pattern associated with anti-NT5c1A. Conclusions: Anti-NT5c1A has moderate sensitivity and high specificity for sIBM using ALBIA. The presence of anti-NT5c1A antibodies may be associated with muscle weakness. Anti-NT5c1A antibodies were not associated with a specific IIF staining pattern, hence screening using HEp-2 substrate is unlikely to be a useful predictor for presence of these autoantibodies.

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“…Novel hIBM mutations are frequently being discovered and gene therapy may be available in the future. [8][9][10] Clinicians should be aware of the most relevant genetic tests available to reach an accurate diagnosis (figure 2).…”

Section: Discussionmentioning

confidence: 99%

Clinical Reasoning: A 40-year-old woman presenting with distal leg weakness

et al. 2019

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A 40-year-old Caucasian woman reported 15 years of progressive lower leg and hand weakness. Weakness began asymmetrically in the legs. She had trouble standing on her toes and developed progressive bilateral foot drop, worse on the right. Over the years, she developed difficulty arising from low seats and climbing stairs. She began falling with her knees buckling bilaterally. She was a hairstylist, but stopped working about 2 years prior after the onset of weakness in her hands, including difficulty opening jars or using scissors. These symptoms progressed insidiously over the years without fluctuation.The patient's medical history was unremarkable and she was not taking medications. Neurologic review of systems was negative for visual changes, dysphagia, dysarthria, pain, stiffness, sensory changes, or bowel/bladder dysfunction. She also denied dyspnea, myalgias, exercise intolerance, or myoglobinuria. All childhood developmental milestones were appropriate. Her parents were not consanguineous and there was no reported family history of weakness or symptoms of nerve or muscle disease.

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New Developments in the Genetics of Inclusion Body Myositis

Cited by 18 publications

References 77 publications

Bioinformatics analysis of gene expression profiles of Inclusion body myositis

Bioinformatics analysis of gene expression profiles of Inclusion body myositis

Anti-NT5c1A Autoantibodies as Biomarkers in Inclusion Body Myositis

Clinical Reasoning: A 40-year-old woman presenting with distal leg weakness

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