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Blood, 15 August 2006, Vol. 108, No. 4, pp. 1320-1327. Prepublished online as a Blood First Edition Paper on May 9, 2006; DOI 10.1182/blood-2005-11-006783. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2005-11-006783v1 108/4/1320    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lobito, A. A Articles by Siegel, R. M Search for Related Content PubMed PubMed Citation Articles by Lobito, A. A Articles by Siegel, R. M Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 16, 2005 Accepted April 10, 2006 Abnormal disulfide-linked oligomerization results in ER retention and altered signaling by TNFR1 mutants in the TNFR1 associated periodic fever syndrome (TRAPS) Adrian A Lobito, Fiona C. Kimberley, Jagan R. Muppidi, Hirsh Komarow, Adrianna J. Jackson, Keith M. Hull, Daniel L. Kastner, Gavin R. Screaton, and Richard M Siegel* Immunoregulation Unit, Autoimmunity Branch, NIAMS, NIH Hammersmith Hospital, Imperial College, London, UK Inflammatory Biology Section, Genetics and Genomics Branch, NIAMS, NIH 3HHMI-NIH Research Scholar, NIH Inflammatory Biology Section, Genetics and Genomics Branch, NIAMS, NIH Inflammatory Biology Section, Genetics and Genomics Branch, NIAMS NIH * Corresponding author; email: siegelr{at}mail.nih.gov. Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autosomal dominant systemic autoinflammatory disease associated with heterozygous mutations in TNF-Receptor 1 (TNFR1). Here we examined the structural and functional alterations caused by nine distinct TRAPS-associated TNFR1 mutations in transfected cells and a mouse 'knock-in' model of TRAPS. We found that these TNFR1 mutants did not generate soluble versions of the receptor, either through membrane cleavage or in exosomes. Mutant receptors did not bind TNF and failed to function as dominant negative inhibitors of TNFR1-induced apoptosis. Instead, TRAPS mutant TNFR1 formed abnormal disulfide-linked oligomers that failed to interact with wild-type TNFR1 molecules through the pre-ligand assembly domain (PLAD) that normally governs receptor self-association. TRAPS mutant TNFR1 molecules were retained intracellularly and colocalized with ER markers. The capacity of mutant receptors to spontaneously induce both apoptosis and NF-? B activity was reduced. In contrast, the R92Q variant of TNFR1 behaved like the wild-type receptor in all of these assays. The inflammatory phenotype of TRAPS may be due to consequences of mutant TNFR1 protein misfolding and ER retention. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. Kumpfel, L-A Hoffmann, H. Pellkofer, W. Pollmann, W. Feneberg, R. Hohlfeld, and P. Lohse Multiple sclerosis and the TNFRSF1A R92Q mutation: Clinical characteristics of 21 cases Neurology, November 25, 2008; 71(22): 1812 - 1820. [Abstract] [Full Text] [PDF] S M Churchman, L D Church, S Savic, L R Coulthard, B Hayward, B Nedjai, M D Turner, R J Mathews, E Baguley, G A Hitman, et al. A novel TNFRSF1A splice mutation associated with increased nuclear factor {kappa}appaB (NF-{kappa}B) transcription factor activation in patients with tumour necrosis factor receptor associated periodic syndrome (TRAPS) Ann Rheum Dis, November 1, 2008; 67(11): 1589 - 1595. [Abstract] [Full Text] [PDF] S Stojanov, C Dejaco, P Lohse, K Huss, C Duftner, B H Belohradsky, M Herold, and M Schirmer Clinical and functional characterisation of a novel TNFRSF1A c.605T>A/V173D cleavage site mutation associated with tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), cardiovascular complications and excellent response to etanercept treatment Ann Rheum Dis, September 1, 2008; 67(9): 1292 - 1298. [Abstract] [Full Text] [PDF] Q. Yao and D. E. Furst Autoinflammatory diseases: an update of clinical and genetic aspects Rheumatology, July 1, 2008; 47(7): 946 - 951. [Abstract] [Full Text] [PDF] S. Farasat, I. Aksentijevich, and J. R. Toro Autoinflammatory Diseases: Clinical and Genetic Advances Arch Dermatol, March 1, 2008; 144(3): 392 - 402. [Abstract] [Full Text] [PDF] A.-S. Dhaunchak and K.-A. Nave A common mechanism of PLP/DM20 misfolding causes cysteine-mediated endoplasmic reticulum retention in oligodendrocytes and Pelizaeus Merzbacher disease PNAS, November 6, 2007; 104(45): 17813 - 17818. [Abstract] [Full Text] [PDF] A. Simon and J. W. M. van der Meer Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2007; 292(1): R86 - R98. [Abstract] [Full Text] [PDF]

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