Two human dwarfing disorders, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED), are caused by mutations in cartilage oligomeric matrix protein (COMP). In PSACH chondrocytes, mutations in COMP lead to the formation of abnormally large rough endoplasmic reticulum (RER) with a unique fingerprint appearance. Located within these vesicles are COMP and type IX collagen. These abnormal vesicles are not found in tendon fibroblasts, although these cells secrete COMP. This proposal is aimed at elucidating the molecular mechanism behind the abnormal retention of COMP and type IX collagen in chondrocytes but not in tendon fibroblasts. The following hypotheses were developed from recent studies: Mutant COMP molecules are retained in the RER of chondrocytes because the type III repeats do not fold properly, which leads to the formation of non-native disulfide bonds. These molecules are then interacting with either chondrocyte specific RER molecules and/or with native type IX collagen and/or type IX collagen chains in the process of assembly. This non-native complex cannot be secreted and leads to the accumulation in lamellar structures within the RER of chondrocytes. Secretion of mutant COMP occurs in fibroblasts and dedifferentiated chondrocytes, because these cells do not synthesize type IX collagen or do not contain chondrocyte specific RER proteins.
Specific aims are proposed to determine the structure of normal and mutant thrombospondin type III repeats, to define the disulfide linkages in these repeats and the effects of calcium on structure, and to test binding interactions of mutant COMP with type IX collagen and unfolded type IX collagen chains and with REER proteins of chondrocytes.
| Vranka, J; Mokashi, A; Keene, D R et al. (2001) Selective intracellular retention of extracellular matrix proteins and chaperones associated with pseudoachondroplasia. Matrix Biol 20:439-50 |
| Maddox, B K; Mokashi, A; Keene, D R et al. (2000) A cartilage oligomeric matrix protein mutation associated with pseudoachondroplasia changes the structural and functional properties of the type 3 domain. J Biol Chem 275:11412-7 |
