A novel form of chondrocyte stress is triggered by a COMP mutation causing pseudoachondroplasia

Autor: Katarzyna A. Piróg, Paul Holden, Benedetta Gualeni, Hannah J Gregson, Farhana Suleman, Matthew Leighton, Sarah M. Edwards, Raymond P. Boot-Handford, Michael D. Briggs
Rok vydání: 2011
Předmět:
musculoskeletal diseases
pseudoachondroplasia
Mutant
Gene Expression
Dwarfism
Apoptosis
Mice
Transgenic
Biology
Endoplasmic Reticulum
medicine.disease_cause
Chondrocyte
Achondroplasia
Multiple epiphyseal dysplasia
Mice
03 medical and health sciences
Pseudoachondroplasia
Chondrocytes
0302 clinical medicine
chondrocyte stress
Genetics
medicine
Animals
Matrilin Proteins
Growth Plate
Research Articles
Genetics (clinical)
Cell Proliferation
Glycoproteins
Oligonucleotide Array Sequence Analysis
030304 developmental biology
Cartilage oligomeric matrix protein
Extracellular Matrix Proteins
0303 health sciences
Mutation
Gene Expression Profiling
cartilage oligomeric matrix protein
Cell Cycle Checkpoints
medicine.disease
Molecular biology
Disease Models
Animal
Oxidative Stress
Phenotype
medicine.anatomical_structure
030220 oncology & carcinogenesis
Unfolded protein response
biology.protein
Zdroj: Human Mutation
ISSN: 1098-1004
1059-7794
Popis: 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.
Databáze: OpenAIRE
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