Mutation (D472Y) in the type 3 repeat domain of cartilage oligomeric matrix protein affects its early vesicle trafficking in endoplasmic reticulum and induces apoptosis.
Cartilage oligomeric matrix protein (COMP) is a large pentameric extracellular glycoprotein found in cartilage, tendon, and synovium, and plays structural roles in cartilage as the fifth member of the thrombospondin family. Familial mutations in type 3 repeats of COMP are known to cause pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (EDM1). Although such mutations induce enlarged rough endoplasmic reticulum (rER) as a morphological change, the metabolic trafficking of mutated COMP remains unclear. In transfected COS7 cells, wild-type COMP was rapidly secreted into culture medium, while the great majority of COMP with the type 3 repeats mutation (D472Y) remained in the cells and a small portion of mutated COMP was secreted. This finding was followed up with a confocal study with an antibody specific to COMP, which demonstrated mutated COMP tightly associated with abnormally enlarged rER. Phosphorylated eIF2alpha, an ER stress protein, was expressed as a pathological reaction in virtually all COS7 cells expressing mutated but not wild-type COMP. Moreover, COS7 cells expressing mutated COMP exhibited significantly more apoptotic reaction than those expressing wild-type COMP. Pathological accumulation of COMP in rER and apoptosis in COS7 cells that were induced by the mutation (D472Y) in COMP imply that COMP mutations play a role in the pathogenesis of PSACH.
Hashimoto
Yusuke
Y
Department of Neuroscience, Institute of Gerontology, Osaka City University Medical School, Osaka, Japan.
Tomiyama
Takami
T
Yamano
Yoshiki
Y
Mori
Hiroshi
H
D000130:Achondroplasia / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019556:COS Cells; D064236:Cartilage Oligomeric Matrix Protein; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D053938:DNA Fragmentation; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D006596:Hexosaminidases / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling; D007719:Knee Joint / Q000033:anatomy & histology; D064235:Matrilin Proteins; D051379:Mice; D017354:Point Mutation; D021381:Protein Transport; D019311:Staurosporine / Q000378:metabolism; D022161:Transport Vesicles / Q000378:metabolism*
D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C577540:Matn1 protein, mouse; D064235:Matrilin Proteins; C577553:TSP5 protein, human; D006596:Hexosaminidases; D019311:Staurosporine