A novel allelic variant of the human TSG-6 gene encoding an amino acid difference in the CUB module. Chromosomal localization, frequency analysis, modeling, and expression

Hilke A. Nentwich, Zehra Mustafa, Marilyn S. Rugg, Brian D. Marsden, Martin R. Cordell, David J. Mahoney, Suzanne C. Jenkins, Barbara Dowling, Erik Fries, Caroline M. Milner, John Loughlin, Anthony J. Day

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Tumor necrosis factor-stimulated gene-6 (TSG-6) encodes a 35-kDa protein, which is comprised of contiguous Link and CUB modules. TSG-6 protein has been detected in the articular joints of osteoarthritis (OA) patients, with little or no constitutive expression in normal adult tissues. It interacts with components of cartilage matrix (e.g. hyaluronan and aggrecan) and thus may be involved in extracellular remodeling during joint disease. In addition, TSG-6 has been found to have anti-inflammatory properties in models of acute and chronic inflammation. Here we have mapped the human TSG-6 gene to 2q23.3, a region of chromosome 2 linked with OA. A single nucleotide polymorphism was identified that involves a non-synonymous G → A transition at nucleotide 431 of the TSG-6 coding sequence, resulting in an Arg to Gln alteration in the CUB module (at residue 144 in the preprotein). Molecular modeling of the CUB domain indicated that this amino acid change might lead to functional differences. Typing of 400 OA cases and 400 controls revealed that the A431 variant identified here is the major TSG-6 allele in Caucasians (with over 75% being A431 homozygotes) but that this polymorphism is not a marker for OA susceptibility in the patients we have studied. Expression of the Arg144 and Gln144 allotypes in Drosophila Schneider 2 cells, and functional characterization, showed that there were no significant differences in the ability of these full-length proteins to bind hyaluronan or form a stable complex with inter-α-inhibitor.
    Original languageEnglish
    Pages (from-to)15354-15362
    Number of pages8
    JournalJournal of Biological Chemistry
    Volume277
    Issue number18
    DOIs
    Publication statusPublished - 3 May 2002

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