Transgenic mice expressing D469Delta mutated cartilage oligomeric matrix protein (COMP) show growth plate abnormalities and sternal malformations.
In humans, mutations in cartilage oligomeric matrix protein (COMP) cause autosomal dominantly inherited skeletal dysplasias. We have generated transgenic mouse lines to study the role of mutant D469Delta COMP in the pathogenesis of pseudoachondroplasia. Biochemical characterization of cartilage tissue demonstrated that transgenic and endogenous COMP subunits were able to form mixed, pentameric molecules in vivo. Mutant COMP was more difficult to extract than the wildtype protein, suggesting an altered anchorage within the matrix. Although both transgenic wildtype and mutant COMP were detected throughout the growth plate, mutant molecules were restricted to the pericellular matrix while wildtype COMP showed a uniform distribution throughout the extracellular matrix. Mice expressing the mutant transgene showed a slight gender specific growth retardation. In mutant animals, the columnar organization in the growth plate was disturbed, proteoglycans were lost and improperly formed collagen fibrils were observed. In some chondrocytes the endoplasmic reticulum was dilated, most probably due to an impaired secretion of mutant COMP similar to that observed in patients. Later in development, the growth plate was irregularly shaped and prematurely invaded by bony tissue. In addition, a fusion of the third and fourth sternebrae was frequently observed.
Schmitz
Markus
M
Center for Biochemistry, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, D-50931 Cologne, Germany.
Niehoff
Anja
A
Miosge
Nicolai
N
Smyth
Neil
N
Paulsson
Mats
M
Zaucke
Frank
F
D000818:Animals; D017209:Apoptosis; D049628:Body Size / Q000235:genetics; D002356:Cartilage / Q000166:cytology / Q000378:metabolism; D064236:Cartilage Oligomeric Matrix Protein; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006132:Growth Plate / Q000002:abnormalities* / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D064235:Matrilin Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D015676:Osteonectin / Q000378:metabolism; D021382:Protein Sorting Signals / Q000235:genetics; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D013249:Sternum / Q000002:abnormalities* / Q000378:metabolism; D013977:Tibia / Q000002:abnormalities / Q000378:metabolism / Q000648:ultrastructure
D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C577540:Matn1 protein, mouse; C577546:Matn3 protein, mouse; D064235:Matrilin Proteins; D015676:Osteonectin; D021382:Protein Sorting Signals; D011509:Proteoglycans; C577553:TSP5 protein, human; D003094:Collagen