title: Pseudoachondroplastic dysplasia: an Iowa review from human to mouse.
abstract: Lamellar inclusions of the rough endoplasmic reticulum in growth plate chondrocytes, first identified (1972) in the Department of Orthopaedic Surgery, University of Iowa, has become the cytochemical hallmark for the pseudoachondroplastic dysplasia (PSACH) phenotype, linking an endoplasmic reticulum storage disorder with the osteochondrodysplasia. Since this original observation, great advances have been made, leading to the molecular understanding of this altered longitudinal bone growth anomaly. A PSACH canine model suggested that abatement of cumulative vertical growth of growth plate chondrocytes seen in PSACH results from (1) altered extracellular matrix constraints for horizontal growth and (2) uncoupling of endochondral and perichondral growth that causes metaphyseal flaring. PSACH, an autosomal dominant disease, is linked to mutation of the cartilage oligomeric matrix protein (COMP) gene. Amino acid substitutions, deletions, or additions is proposed to alter COMP structure that cause its retention in the rough endoplasmic reticulum of growth plate chondrocytes, leading to (1) compositional and structural change of the extracellular matrix, and (2) altered cellular proliferation and volume expansion. Normal growth and development occurs in COMP gene knockout mice that do not synthesis COMP, demonstrating that a mutant COMP, not absence of COMP, is required for the PSACH phenotype. The mechanism by which mutant COMP induces a PSACH phenotype remains to be elucidated. At the University of Iowa a cell culture system has been developed whereby mutant COMP transgenes are introduced into chondrocytes and the expressed product COMP is retained in the endoplasmic reticulum. This readily manipulated system makes it possible to decipher systematically the system's cellular secretory processing pathway, in order to clarify the mechanism(s) by which the mutant COMP is retained within the endoplasmic reticulum. Concurrent with this is the development of transgenic mice expressing the mutant COMP used in the cell culture system. This will make it possible to establish that expression of a human PSACH-linked mutant COMP will produce a PSACH phenotype. A PSACH animal model will provide a means to characterize the mechanism of altered longitudinal bone growth and to test gene therapy approaches for correcting the anomaly.
authors.affiliation: Department of Orthopaedic Surgery, The University of Iowa, Iowa City 52242-1181, USA. jeff-stevens@uiowa.edu
authors.forename: J W
authors.initials: JW
authors.lastname: Stevens
mesh_terms: D000818:Animals; D064236:Cartilage Oligomeric Matrix Protein; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004285:Dogs; D016326:Extracellular Matrix Proteins / Q000235:genetics; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007484:Iowa; D064235:Matrilin Proteins; D051379:Mice; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics*; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D019699:Thrombospondins / Q000235:genetics
chemical_list: D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C577540:Matn1 protein, mouse; D064235:Matrilin Proteins; C577553:TSP5 protein, human; D019699:Thrombospondins