title: 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.
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 A(431) variant identified here is the major TSG-6 allele in Caucasians (with over 75% being A(431) homozygotes) but that this polymorphism is not a marker for OA susceptibility in the patients we have studied. Expression of the Arg(144) and Gln(144) 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-alpha-inhibitor.
authors.affiliation: Medical Research Council Immunochemistry Unit, University of Oxford, South Parks Rd., Oxford OX1 3QU, United Kingdom.
authors.forename: Hilke A
authors.initials: HA
authors.lastname: Nentwich
authors.forename: Zehra
authors.initials: Z
authors.lastname: Mustafa
authors.forename: Marilyn S
authors.initials: MS
authors.lastname: Rugg
authors.forename: Brian D
authors.initials: BD
authors.lastname: Marsden
authors.forename: Martin R
authors.initials: MR
authors.lastname: Cordell
authors.forename: David J
authors.initials: DJ
authors.lastname: Mahoney
authors.forename: Suzanne C
authors.initials: SC
authors.lastname: Jenkins
authors.forename: Barbara
authors.initials: B
authors.lastname: Dowling
authors.forename: Erik
authors.initials: E
authors.lastname: Fries
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Milner
authors.forename: John
authors.initials: J
authors.lastname: Loughlin
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Day
mesh_terms: D000225:Adenine; D000409:Alanine; D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001120:Arginine; D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000235:genetics*; D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2; D005787:Gene Frequency; D008040:Genetic Linkage; D014644:Genetic Variation; D005973:Glutamine; D006147:Guanine; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010003:Osteoarthritis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D015815:Cell Adhesion Molecules; C072273:TNFAIP6 protein, human; D014409:Tumor Necrosis Factor-alpha; D005973:Glutamine; D006147:Guanine; D001120:Arginine; D000225:Adenine; D000409:Alanine