title: Role of TSP-5/COMP in pseudoachondroplasia.
abstract: Pseudoachondroplasia (PSACH) is a well-characterized dwarfing condition associated with disproportionate short stature, abnormal joints and osteoarthritis requiring joint replacement. PSACH is caused by mutations in cartilage oligomeric matrix protein (COMP). COMP, the fifth member of the thrombospondin (TSP) gene family, is a pentameric protein found primarily in the extracellular matrix of musculoskeletal tissues. Functional studies have shown that COMP binds types II and IX collagens but the role of COMP in the extracellular matrix remains to be defined. Mutations in COMP interfere with calcium-binding and protein conformation. PSACH growth plate and growth plate chondrocytes studies indicate that COMP mutations have a dominant negative effect with both COMP and type IX collagen being retained in large rER cisternae. This massive retention causes impaired chondrocyte function with little COMP secreted into the matrix and premature loss of chondrocytes. Deficiency of linear growth results from loss of chondrocytes from the growth plate. Secondarily, the matrix contains minimal COMP, which may be normal and/or mutant, and little type IX collagen. This deficiency results in abnormal joints that are easily eroded and cause painful osteoarthritis. Unlike other misfolded proteins that are targeted for degradation, much of the retained COMP escapes degradation, compromises cell function, and causes cell death. Gene therapy will need to target the reduction of COMP in order to restore normal chondrocyte function and longevity.
authors.affiliation: Department of Pediatrics, Medical School at Houston, University of Texas Health Science Center, 6431 Fannin, Room MSB 3.306, Houston, TX 77030, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Posey
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hayes
authors.forename: Richard
authors.initials: R
authors.lastname: Haynes
authors.forename: Jacqueline T
authors.initials: JT
authors.lastname: Hecht
mesh_terms: D000130:Achondroplasia / Q000235:genetics / Q000628:therapy; D064236:Cartilage Oligomeric Matrix Protein; D019902:Chondrocytes / Q000473:pathology; D004392:Dwarfism / Q000235:genetics* / Q000628:therapy; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D064235:Matrilin Proteins; D009154:Mutation / Q000235:genetics; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000628:therapy; D017434:Protein Structure, Tertiary / Q000235:genetics; D019699:Thrombospondins / Q000235:genetics
chemical_list: D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D064235:Matrilin Proteins; C577553:TSP5 protein, human; D019699:Thrombospondins