title: Selective intracellular retention of extracellular matrix proteins and chaperones associated with pseudoachondroplasia.
abstract: Mutations in the cartilage oligomeric matrix protein (COMP) gene result in pseudoachondroplasia (PSACH), which is a chondrodysplasia characterized by early-onset osteoarthritis and short stature. COMP is a secreted pentameric glycoprotein that belongs to the thrombospondin family of proteins. We have identified a novel missense mutation which substitutes a glycine for an aspartic acid residue in the thrombospondin (TSP) type 3 calcium-binding domain of COMP in a patient diagnosed with PSACH. Immunohistochemistry and immunoelectron microscopy both show abnormal retention of COMP within characteristically enlarged rER inclusions of PSACH chondrocytes, as well as retention of fibromodulin, decorin and types IX, XI and XII collagen. Aggrecan and types II and VI collagen were not retained intracellularly within the same cells. In addition to selective extracellular matrix components, the chaperones HSP47, protein disulfide isomerase (PDI) and calnexin were localized at elevated levels within the rER vesicles of PSACH chondrocytes, suggesting that they may play a role in the cellular retention of mutant COMP molecules. Whether the aberrant rER inclusions in PSACH chondrocytes are a direct consequence of chaperone-mediated retention of mutant COMP or are otherwise due to selective intracellular protein interactions, which may in turn lead to aggregation within the rER, is unclear. However, our data demonstrate that retention of mutant COMP molecules results in the selective retention of ECM molecules and molecular chaperones, indicating the existence of distinct secretory pathways or ER-sorting mechanisms for matrix molecules, a process mediated by their association with various molecular chaperones.
authors.affiliation: Research Department, Shriners Hospital for Children, Portland, OR 97201, USA.
authors.forename: J
authors.initials: J
authors.lastname: Vranka
authors.forename: A
authors.initials: A
authors.lastname: Mokashi
authors.forename: D R
authors.initials: DR
authors.lastname: Keene
authors.forename: S
authors.initials: S
authors.lastname: Tufa
authors.forename: G
authors.initials: G
authors.lastname: Corson
authors.forename: M
authors.initials: M
authors.lastname: Sussman
authors.forename: W A
authors.initials: WA
authors.lastname: Horton
authors.forename: K
authors.initials: K
authors.lastname: Maddox
authors.forename: L
authors.initials: L
authors.lastname: Sakai
authors.forename: H P
authors.initials: HP
authors.lastname: Bächinger
mesh_terms: D053674:Aggrecans; D002135:Calcium-Binding Proteins / Q000378:metabolism; D037281:Calnexin; D002352:Carrier Proteins / Q000378:metabolism; D002356:Cartilage / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D064236:Cartilage Oligomeric Matrix Protein; D002648:Child; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004252:DNA Mutational Analysis; D058575:Decorin; D018870:Endoplasmic Reticulum, Rough / Q000378:metabolism / Q000648:ultrastructure; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D000071235:Fibromodulin; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D050958:HSP47 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology / Q000648:ultrastructure; D007424:Intracellular Fluid / Q000378:metabolism; D037181:Lectins, C-Type; D064235:Matrilin Proteins; D018832:Molecular Chaperones / Q000378:metabolism*; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D010009:Osteochondrodysplasias / Q000378:metabolism* / Q000473:pathology; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism
chemical_list: D053674:Aggrecans; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D064236:Cartilage Oligomeric Matrix Protein; D011508:Chondroitin Sulfate Proteoglycans; C546878:DCN protein, human; D058575:Decorin; D016326:Extracellular Matrix Proteins; C000604330:FMOD protein, human; D006023:Glycoproteins; D050958:HSP47 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D037181:Lectins, C-Type; D064235:Matrilin Proteins; D018832:Molecular Chaperones; D011509:Proteoglycans; C494660:SERPINH1 protein, human; C577553:TSP5 protein, human; D000071235:Fibromodulin; D037281:Calnexin; D003094:Collagen; D019704:Protein Disulfide-Isomerases