A mutation in the gene encoding the α2 chain of the fibril-associated collagen IX, COL9A2, causes multiple epiphyseal dysplasia (EDM2)

Muragaki, Yasuteru; Mariman, E.C.M.; Beersum, Sylvia E. C. van; Perälä, Merja; Mourik, J. B. A. van; Warman, Matthew L.; Olsen, Bjørn R.; Hamel, B.C.J.

doi:10.1038/ng0196-103

Cited by 192 publications

(133 citation statements)

References 19 publications

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“…In humans, mutations in cartilage matrix proteins often cause osteochondrodysplasias with various degrees of severity. Mutations in each of the three collagen IX ␣ chains can cause the human disease multiple epiphyseal dysplasia (MED) (8,36,38). However, the complete loss of collagen IX, as in the mouse knockout, does not lead to the development of MED.…”

Section: Vol 25 2005 Matrilin-3 In Collagen Ix-deficient Mice 10473mentioning

confidence: 99%

Altered Integration of Matrilin-3 into Cartilage Extracellular Matrix in the Absence of Collagen IX

Budde

Blumbach²,

Ylöstalo

et al. 2005

Molecular and Cellular Biology

134

157

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The matrilins are a family of four noncollagenous oligomeric extracellular matrix proteins with a modular structure. Matrilins can act as adapters which bridge different macromolecular networks. We therefore investigated the effect of collagen IX deficiency on matrilin-3 integration into cartilage tissues. Mice harboring a deleted Col9a1 gene lack synthesis of a functional protein and produce cartilage fibrils completely devoid of collagen IX. Newborn collagen IX knockout mice exhibited significantly decreased matrilin-3 and cartilage oligomeric matrix protein (COMP) signals, particularly in the cartilage primordium of vertebral bodies and ribs. In the absence of collagen IX, a substantial amount of matrilin-3 is released into the medium of cultured chondrocytes instead of being integrated into the cell layer as in wild-type and COMP-deficient cells. Gene expression of matrilin-3 is not affected in the absence of collagen IX, but protein extraction from cartilage is greatly facilitated. Matrilin-3 interacts with collagen IX-containing cartilage fibrils, while fibrils from collagen IX knockout mice lack matrilin-3, and COMP-deficient fibrils exhibit an intermediate integration. In summary, the integration of matrilin-3 into cartilage fibrils occurs both by a direct interaction with collagen IX and indirectly with COMP serving as an adapter. Matrilin-3 can be considered as an interface component, capable of interconnecting macromolecular networks and mediating interactions between cartilage fibrils and the extrafibrillar matrix.

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Section: Vol 25 2005 Matrilin-3 In Collagen Ix-deficient Mice 10473mentioning

confidence: 99%

Altered Integration of Matrilin-3 into Cartilage Extracellular Matrix in the Absence of Collagen IX

Budde

Blumbach²,

Ylöstalo

et al. 2005

Molecular and Cellular Biology

134

157

View full text Add to dashboard Cite

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“…This form of MED (EDM2) was mapped to chromosome 1p32, and the locus was identified as the COL9A2. Mutations have been identified in COL9A2 (11). A third MED locus has recently been mapped to COL93A, and a mutation was identified (12).…”

Section: Cartilage Oligomeric Matrix Protein (Comp)mentioning

confidence: 99%

A Cartilage Oligomeric Matrix Protein Mutation Associated with Pseudoachondroplasia Changes the Structural and Functional Properties of the Type 3 Domain

Maddox¹,

Mokashi²,

Keene³

et al. 2000

Journal of Biological Chemistry

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Cartilage oligomeric matrix protein (COMP) is a member of the thrombospondin family of extracellular matrix glycoproteins. All members of the family contain a highly conserved region of thrombospondin type 3 sequence repeats that bind calcium. A mutation in COMP previously identified in a patient with pseudoachondroplasia resulted in abnormal sequestration of COMP in distinctive rER vesicles. The mutation, Asp-446 3 Asn, is located in the type 3 repeats of the molecule. This region was expressed in a mammalian culture with and without the mutation to study the structural or functional properties associated with the mutation. The biophysical parameters of the mutant peptide were compared with those of the wild type and revealed the following difference: secondary structural analysis by circular dichroism showed more ␣-helix content in the wild-type peptides. The calcium binding properties of the two peptides were significantly different; there were 17 calcium ions bound/wild-type COMP3 peptide compared with 8/mutant peptide. In addition, wild-type COMP3 had a higher affinity for calcium and bound calcium more cooperatively. Calcium bound by the wild-type peptide was reflected in a structural change as indicted by velocity sedimentation. Thus, the effect of the COMP mutation appears to profoundly alter the calcium binding properties and may account for the difference observed in the structure of the type 3 domain. Furthermore, the highly cooperative binding of calcium to COMP3 suggests that these type 3 sequence repeats form a single protein domain, the thrombospondin type 3 domain.

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“…Collagen IX is essential for the normal structure and function of cartilage. Its mutations in man cause multiple epiphyseal dysplasia (7)(8)(9)(10)(11)(12)(13) and in mouse cause degenerative changes in articular cartilage (14,15).…”

mentioning

confidence: 99%

The Fibril-associated Collagen IX Provides a Novel Mechanism for Cell Adhesion to Cartilaginous Matrix

Käpylä

Jäälinoja

Tulla

et al. 2004

Journal of Biological Chemistry

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Collagen IX is the prototype fibril-associated collagen with interruptions in triple helix. In human cartilage it covers collagen fibrils, but its putative cellular receptors have been unknown. The reverse transcription-PCR analysis of human fetal tissues suggested that based on their distribution all four collagen receptor integrins, namely ␣ 1 ␤ 1 , ␣ 2 ␤ 1 , ␣ 10 ␤ 1 , and ␣ 11 ␤ 1 , are possible receptors for collagen IX. Furthermore primary chondrocytes and chondrosarcoma cells express the four integrins simultaneously. Chondrosarcoma cells, as well as Chinese hamster ovary cells transfected to express ␣ 1 ␤ 1 , ␣ 2 ␤ 1 , or ␣ 10 ␤ 1 integrin as their only collagen receptor, showed fast attachment and spreading on human recombinant collagen IX indicating that it is an effective cell adhesion protein. To further study the recognition of collagen IX we produced recombinant ␣I domains in Escherichia coli. For each of the four ␣I domains, collagen IX was among the best collagenous ligands, making collagen IX exceptional compared with all other collagen subtypes tested so far. Rotary shadowing electron microscopy images of both ␣ 1 I-and ␣ 2 Icollagen IX complexes unveiled only one binding site located in the COL3 domain close to the kink between it and the COL2 domain. The recognition of collagen IX by ␣ 2 I was considered to represent a novel mechanism for two reasons. First, collagen IX has no GFOGER motif, and the identified binding region lacks any similar sequences. Second, the ␣ 2 I domain mutations D219R and H258V, which both decreased binding to collagen I and GFOGER, had very different effects on its binding to collagen IX. D219R had no effect, and H258V prevented type IX binding. Thus, our results indicate that collagen IX has unique cell adhesion properties when compared with other collagens, and it provides a novel mechanism for cell adhesion to cartilaginous matrix.Collagen IX was the first member to be discovered of a subgroup of collagens, now known as the fibril-associated collagens with interrupted triple helix (FACITs) 1 (1). At the present, FACITs also include collagens XII, XIV, XVI, XIX, XX, XXI, and XXII. Collagen IX is composed of three different ␣ chains, termed ␣1(IX), ␣2(IX), and ␣3(IX). Structurally the collagen IX molecule can be divided into three triple helical domains (COL1, COL2, and COL3) separated and flanked by non-triple helical (NC) domains. Collagen IX is expressed in cartilage and in a limited number of other locations, including developing eye. Collagen IX can be covalently cross-linked to collagen II, and typically it covers the large fibrils formed by collagens II and XI (2-5). There is a kink between COL2 and COL3 domains making the COL3 domain project into the perifibrillar space, whereas the COL1 and COL2 domains are arranged on the surface of the fibril. Many but not all collagen IX molecules are proteoglycans because a glycosaminoglycan (GAG) chain may be attached to NC3 domain via a serine residue in the ␣2(IX) chain (6). Collagen IX is essential for the normal st...

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A mutation in the gene encoding the α2 chain of the fibril-associated collagen IX, COL9A2, causes multiple epiphyseal dysplasia (EDM2)

Abstract: A mutation in the gene encoding the a2 chain of the fibril-associated collagen IX, COL9A2, causes multiple epiphyseal dysplasia (EDM2)

Cited by 192 publications

References 19 publications

Altered Integration of Matrilin-3 into Cartilage Extracellular Matrix in the Absence of Collagen IX

Altered Integration of Matrilin-3 into Cartilage Extracellular Matrix in the Absence of Collagen IX

A Cartilage Oligomeric Matrix Protein Mutation Associated with Pseudoachondroplasia Changes the Structural and Functional Properties of the Type 3 Domain

The Fibril-associated Collagen IX Provides a Novel Mechanism for Cell Adhesion to Cartilaginous Matrix

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