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Functional Consequences of Disease-Associated Mutations in TNFR1 Elucidated by Transcriptome Analysis

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Advances in TNF Family Research

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 691))

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Abstract

Mutations in the TNFRSF1A (TNF receptor 1) gene cause the autosomal dominant, autoinflammatory tumour necrosis factor receptor-associated periodic syndrome (TRAPS). TRAPS is characterised by recurring attacks of fever, abdominal pain, arthralgia, myalgia, conjunctivitis, migratory skin lesions and systemic amyloidosis. The exact mechanism by which this periodic fever is triggered has yet to be elucidated. Over the last decade, several studies with patient and transfected cells have attempted to dissect the molecular mechanisms induced by mutant receptor expression and resulted in several hypotheses being proposed to explain the disease pathogenesis. Our recent data suggest that cellular expression of mutant TNFR1 per se is a signal for inflammatory changes. We hypothesised that different mutations can lead to the activation of distinct intracellular signalling pathways with a pro-inflammatory outcome in a TNF-independent fashion. To test this hypothesis, we investigated how different TNFR1 mutants affect global gene expression in epithelial and endothelial cell models. Compared to WT, cells expressing mutant TNFR1 showed downregulation of genes that suppress immune responses and upregulation of multiple genes involved in mediating inflammation. Both cell type-specific and mutant-specific profiles were identified. We have identified a number of novel genes that may play a role in the pathogenesis of TRAPS. Further studies with patient cells and in vivo models are needed to clarify relevance for disease pathogenesis and assist in the identification of new drug targets.

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Authors and Affiliations

  1. Institute of Infection, Immunity & Inflammation, and School of Molecular Medical Sciences, University of Nottingham; Immunology, A Floor West Block, Queen’s Medical Centre, Nottingham, NG7 2UH, UK

    Susana L. Rebelo, Paul M. Radford, Susan E. Bainbridge, Ian Todd & Patrick J. Tighe

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  1. Susana L. Rebelo
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  2. Paul M. Radford
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  3. Susan E. Bainbridge
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  4. Ian Todd
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  5. Patrick J. Tighe
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Correspondence to Susana L. Rebelo .

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Editors and Affiliations

  1. Dept. Biological Chemistry, Weizmann Institute of Science, 1 Herzl Street, Rehovot, 76100, Israel

    David Wallach

  2. Dept. Biological Chemistry, Weizmann Institute of Science, 1 Herzl Street, Rehovot, 76100, Israel

    Andrew Kovalenko

  3. Kennedy Institute of Rheumatology, Imperial College London, Aspenlea Rd. 1, London, W6 8LH, United Kingdom

    Marc Feldmann

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Rebelo, S.L., Radford, P.M., Bainbridge, S.E., Todd, I., Tighe, P.J. (2011). Functional Consequences of Disease-Associated Mutations in TNFR1 Elucidated by Transcriptome Analysis. In: Wallach, D., Kovalenko, A., Feldmann, M. (eds) Advances in TNF Family Research. Advances in Experimental Medicine and Biology, vol 691. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6612-4_47

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