Communicated by Iain McIntosh
A novel form of chondrocyte stress is triggered by a COMP mutation causing pseudoachondroplasia†
Article first published online: 17 NOV 2011
© 2011 Wiley Periodicals, Inc.
Volume 33, Issue 1, pages 218–231, January 2012
How to Cite
Suleman, F., Gualeni, B., Gregson, H. J., Leighton, M. P., Piróg, K. A., Edwards, S., Holden, P., Boot-Handford, R. P. and Briggs, M. D. (2012), A novel form of chondrocyte stress is triggered by a COMP mutation causing pseudoachondroplasia. Hum. Mutat., 33: 218–231. doi: 10.1002/humu.21631
- Issue published online: 14 DEC 2011
- Article first published online: 17 NOV 2011
- Accepted manuscript online: 17 OCT 2011 09:28AM EST
- Manuscript Accepted: 16 SEP 2011
- Manuscript Received: 21 JUL 2011
- Wellcome Trust. Grant Number: Grants 071161/Z/03/Z, 084353/Z/07/Z, and 078456/Z/05/Z
- cartilage oligomeric matrix protein;
- chondrocyte stress
Pseudoachondroplasia (PSACH) results from mutations in cartilage oligomeric matrix protein (COMP) and the p.D469del mutation within the type III repeats of COMP accounts for approximately 30% of PSACH. To determine disease mechanisms of PSACH in vivo, we introduced the Comp D469del mutation into the mouse genome. Mutant animals were normal at birth but grew slower than their wild-type littermates and developed short-limb dwarfism. In the growth plates of mutant mice chondrocyte columns were reduced in number and poorly organized, while mutant COMP was retained within the endoplasmic reticulum (ER) of cells. Chondrocyte proliferation was reduced and apoptosis was both increased and spatially dysregulated. Previous studies on COMP mutations have shown mutant COMP is co-localized with chaperone proteins, and we have reported an unfolded protein response (UPR) in mouse models of PSACH-MED (multiple epiphyseal dysplasia) harboring mutations in Comp (T585M) and Matn3, Comp etc (V194D). However, we found no evidence of UPR in this mouse model of PSACH. In contrast, microarray analysis identified expression changes in groups of genes implicated in oxidative stress, cell cycle regulation, and apoptosis, which is consistent with the chondrocyte pathology. Overall, these data suggest that a novel form of chondrocyte stress triggered by the expression of mutant COMP is central to the pathogenesis of PSACH. Hum Mutat 33:218–231, 2012. © 2011 Wiley Periodicals, Inc.