Collagen II containing a cys substitution for Arg-α1-519. Homotrimeric monomers containing the mutation do not assemble into fibrils but alter the self-assembly of the normal protein

Department of Biochemistry and Molecular Biology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 04/1997; 272(10):6457-64. DOI: 10.1074/jbc.272.10.6457
Source: PubMed


A recombinant system was used to prepare human type II procollagen containing the substitution of Cys for Arg at alpha1-519 found in three unrelated families with early onset generalized osteoarthritis together with features of a mild chondrodysplasia probably best classified as spondyloepiphyseal dysplasia. In contrast to mutated procollagens containing Cys substitutions for obligatory Gly residues, the Cys substitution at alpha1-519 did not generate any intramolecular disulfide bonds. The results were consistent with computer modeling experiments that demonstrated that the alpha carbon distances were shorter with Cys substitutions for obligatory Gly residues than with Cys substitutions in the Y position residues in repeating -Gly-X-Y- sequences of the collagen triple helix. The mutated collagen did not assemble into fibrils under conditions in which the normal monomers polymerized. However, the presence of the mutated monomer in mixtures with normal collagen II increased the lag time for fibril assembly and altered the morphology of the fibrils formed.

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    • "The first structural genes analyzed were genes coding for major cartilage collagens II, IX, and XI, where mutations causing Stickler syndrome, a mild chondrodysplasia associated with OA, have been identified (for a review, see Robin et al. (2010)). Earlier reports suggested linkage between COL2A1 and OA in two large families (Palotie et al. 1989; Vikkula et al. 1993), and a causal Arg519Cys mutation in the 1(II) chain was identified in OA families (Ala-Kokko et al. 1990; Fertala et al. 1997). In addition rare sequence variants in the genes for collagens II and XI have been associated with hip/knee OA (Jakkula et al. 2005 "

    Principles of Osteoarthritis- Its Definition, Character, Derivation and Modality-Related Recognition, 02/2012; , ISBN: 978-953-51-0063-8
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    • "Alternatively, the chondrocyte response to mechanical stress in an abnormal matrix structure may result in different patterns of structural protein expression, dedifferentiation, hypertrophy, regeneration, and an abnormal pyrophosphate synthesis [91]. In addition, mutations in structural genes may lead to changes in molecular interactions between various components of the extracellular matrix, altering the thickness and three-dimensional organization of the cartilage collagen fibrils and destabilizing the cartilaginous matrix [92-94]. One of the curious features of OA associated with mutations in genes encoding structural matrix proteins is the selectivity with which different joints may be affected. "
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    ABSTRACT: The Arg5l9-Cys mutation in type II collagen results in severe, precocious familial osteoarthritis (OA) in 100% of carriers within the first 3 decades of life. The carrier population provided a well-defined patient population for the study of serum markers of familial OA with respect to pathogenesis, diagnosis, and prognosis. Serum was obtained from 31 mutation-positive individuals and 16 mutation-negative individuals. OA severity was determined by clinical and radiologic assessments. Levels of serum cartilage oligomeric matrix protein (COMP), keratan sulfate (KS) epitope, the 846 epitope of aggrecan, and the C propeptide of type II collagen (CPII) were measured and were correlated with the radiologic findings. COMP and KS levels, both of which have been suggested to be indicative of disturbed cartilage turnover, were significantly elevated in mutation-positive individuals and in the individuals with OA regardless of mutation status. There was no statistically significant difference between mutation-positive, mutation-negative, OA-positive, and OA-negative individuals with respect to serum concentrations of epitope 846 or CPII, both of which are putative markers of cartilage repair. Study of the macromolecular constituents of cartilage released into serum in subjects with familial OA revealed altered metabolism in OA, as demonstrated by elevated COMP and KS levels. Other constituents, the 846 epitope and CPII, were not altered, indicating dissociation of cartilage anabolism and breakdown. Future sequential studies will provide an opportunity to define biochemical changes as familial OA develops and to monitor therapeutic responses.
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