Intron-derived aberrant splicing of A20 transcript in rheumatoid arthritis.
Objective. Aberrant splicing is one of the most significant components generating functional diversity in many pathological conditions. The objective of this study was to analyse the mutations or aberrant splicing of A20 transcript, the region encompassing the ovarian tumour (OTU) domain [which is f...
| Publicado en: | Rheumatology Vol. 52; no. 3; pp. 427 - 438 |
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| Autores principales: | , , , , , , , , , , , , , |
| Formato: | pictorial research tables/charts Journal Article |
| Publicado: |
Oxford University Press / USA
Mar2013
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=85655770&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 85655770 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 14620324 DN9 jtl: Rheumatology issn: 14620324 maglogo: N pubinfo: dt: Mar2013 vid: 52 iid: 3 pid: 622 pub: Oxford University Press / USA artinfo: ui: 85655770 104236961 104236961 10.1093/rheumatology/kes292 85655770 ppf: 427 ppct: 11 formats: tig: atl: Intron-derived aberrant splicing of A20 transcript in rheumatoid arthritis. aug: au: Yoon, Hyun Kyung Byun, Hee Sun Lee, Hyunji Jeon, Juhee Lee, Yoonjung Li, Yuwen Jin, Eun-Heui Kim, Jaewoo Hong, Jang Hee Kim, Jin Hyun Seok, Jeong Ho Kang, Seong Wook Lee, Won Hyung Hur, Gang Min affil: Department of Pharmacology sug: subj: Arthritis, Rheumatoid Familial and Genetic Tumor Necrosis Factor Adverse Effects Cytokines Physiology Human South Korea Academic Medical Centers Reverse Transcriptase Polymerase Chain Reaction Mutation Immunoblotting Equipment and Supplies ab: Objective. Aberrant splicing is one of the most significant components generating functional diversity in many pathological conditions. The objective of this study was to analyse the mutations or aberrant splicing of A20 transcript, the region encompassing the ovarian tumour (OTU) domain [which is functionally important as an inhibitor of nuclear factor (NF)-κB activation] in fibroblast-like synoviocytes (FLSs) from RA patients.Methods. Alterations in A20 transcripts were determined through sequence analysis of 10 clones of A20 cDNA in FLSs from each of the five RA patients. The levels of aberrant A20 transcript were measured by quantitative real-time RT–PCR with primers to specifically recognize the inserted introns. The functional role of A20 and its aberrant variants were examined by analysing NF-κB luciferase reporter activity and NF-κB-dependent target gene expression.Results. In RA FLSs, we discovered four novel aberrant A20 transcripts, most of which resulted from insertion of partial intron 2, intron 4 and/or deletion of exon 4. In each of these FLSs, sequence analysis revealed that these aberrant insertional sequences were flanked by consensus splice donor and acceptor sequences without nucleotide substitution, suggesting alternative splicing as the likely mutational mechanism. These variants elicited a codon frame shift by creating a premature translational stop codon, and eventually, disruption of the OTU domain (which is functionally important as an inhibitor of NF-κB activation) of A20. The expression level of aberrant A20 transcript was correlated well with persisitently enhanced status of NF-κB signalling, as evident by the phosphorylation of inhibitor of NF-κB (IκB)-α and transcription of NF-κB target genes.Conclusion. The results suggest that A20 inactivation by the novel aberrant splicing may contribute to RA progression by inducing persistent NF-κB activation. pubtype: Academic Journal doctype: pictorial research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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