Rittore, C, Sanchez, E, Soler, S et al. (6 more authors) (2013) Identification of a new exon 2-skipped TNFR1 transcript: Regulation by three functional polymorphisms of the TNFR-associated periodic syndrome (TRAPS) gene. Annals of the Rheumatic Diseases, 73 (1). 290 - 297. ISSN 0003-4967
Abstract
Background: Mutations in the TNFRSF1A gene encoding the tumour necrosis factor a cell surface receptor, TNFR1, cause TNFR-associated periodic syndrome (TRAPS) and polymorphisms in TNFRSF1A, including rs4149570, rs767455 and rs1800692, are associated with inflammatory diseases. Objectives: To describe a new exon 2-spliced transcript-TNFR1-d2-and the impact of these three single nucleotide polymorphisms on exon 2 splicing, transcriptional activity of TNFRSF1A and TRAPS phenotype. Methods: Expression of TNFRSF1A transcripts was performed by reverse-transcription-PCR in a range of human cells and tissues. Exon 2 splicing and transcriptional activity were analysed in HEK293T and SW480 cells by in vitro alternative splicing and luciferase assays, respectively. We constructed haplotypes containing rs4149570, rs767455 and rs1800692 in controls (n=72), patients with TRAPS (n=111) and in TRAPS-like patients (n=450) to compare their distribution and association with clinical features of TRAPS. Results: TNFR1-d2 was expressed in a tissue-specific manner, whereas TNFR1 expression was ubiquitous. Alternative splicing assays showed that the T-A-T haplotype at rs4149570-rs767455-rs1800692 had a significantly higher expression of exon 2-skipping product (p=0.02) compared with the G-G-C haplotype. Transcriptional activity from the T-T haplotype at rs4149570-rs1800692 was increased compared with the G-C haplotype (p=0.03). In patients with TRAPS, rs1800692 T/T homozygotes were excessively rare (p<10) and TRAPS-like patients with this genotype experienced less fever. Conclusions: Our study provides a new mechanism of TNFRSF1A regulation whereby three polymorphisms in the promoter, exon 1 and intron 4 have a functional and combined effect on exon 2 splicing, via a coupling mechanism between transcription and splicing. These polymorphisms may affect the phenotype of TRAPS and TRAPS-like patients.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) 2013, The Authors. This is an author produced version of a paper published in Annals of the Rheumatic Diseases. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Institute of Rheumatology & Musculoskeletal Medicine (LIRMM) (Leeds) > Experimental Musculoskeletal Medicine (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 18 Aug 2015 14:31 |
Last Modified: | 06 Nov 2017 03:48 |
Published Version: | http://dx.doi.org/10.1136/annrheumdis-2012-203023 |
Status: | Published |
Publisher: | BMJ Publishing Group |
Identification Number: | 10.1136/annrheumdis-2012-203023 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:86516 |