title: Activation of the innate immune response and interferon signalling in myotonic dystrophy type 1 and type 2 cataracts.
abstract: Myotonic dystrophy (DM) is caused by a triplet repeat expansion in the non-coding region of either the DMPK (DM1) or CNBP (DM2) gene. Transcription of the expanded region causes accumulation of double-stranded RNA (dsRNA) in DM cells. We sought to determine how expression of triplet repeat RNA causes the varied phenotype typical of DM. Global transcription was measured in DM and non-DM cataract samples using Illumina Bead Arrays. DM samples were compared with non-DM samples and lists of differentially expressed genes (P≤ 0.05) were prepared. Gene set enrichment analysis and the Interferome database were used to search for significant patterns of gene expression in DM cells. Expression of individual genes was measured using quantitative real-time polymerase chain reaction. DMPK and CNBP expression was confirmed in native lens cells showing that a toxic RNA gain of function mechanism could exist in lens. A high proportion, 83% in DM1 and 75% in DM2, of the significantly disregulated genes were shared by both forms of the disease, suggesting a common mechanism. The upregulated genes in DM1 and DM2 were highly enriched in both interferon-regulated genes (IRGs) and genes associated with the response to dsRNA and the innate immune response. The characteristic fingerprint of IRGs and the signalling pathways identified in lens cells support a role for dsRNA activation of the innate immune response in the pathology of DM. This new evidence forms the basis for a novel hypothesis to explain the complex mechanism of DM.
authors: School of Biological Sciences, University of East Anglia, Norwich, UK. j.rhodes@uea.ac.uk
authors: Jeremy D
authors: JD
authors: Rhodes
authors: Martin C
authors: MC
authors: Lott
authors: Sarah L
authors: SL
authors: Russell
authors: Vincent
authors: V
authors: Moulton
authors: Julie
authors: J
authors: Sanderson
authors: I Michael
authors: IM
authors: Wormstone
authors: David C
authors: DC
authors: Broadway
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002386:Cataract / Q000209:etiology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007372:Interferons / Q000276:immunology / Q000378:metabolism*; D007908:Lens, Crystalline / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020967:Myotonic Disorders / Q000150:complications* / Q000235:genetics; D009223:Myotonic Dystrophy / Q000150:complications* / Q000235:genetics; D065636:Myotonin-Protein Kinase; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome / Q000235:genetics
chemical_list: C433227:CNBP protein, human; C585517:DMPK protein, human; D018398:Homeodomain Proteins; D016601:RNA-Binding Proteins; C106687:SIX5 protein, human; D007372:Interferons; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases