University of Oulu

Defects in the genes coding for cartilage extracellular matrix proteins as a cause of osteoarthritis and multiple epiphyseal dysplasia

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Author: Jakkula, Eveliina1,2
Organizations: 1University of Oulu, Faculty of Medicine, Department of Medical Biochemistry and Molecular Biology
2University of Oulu, Biocenter Oulu
Format: ebook
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1 MB)
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Language: English
Published: 2005
Publish Date: 2005-05-17
Thesis type: Doctoral Dissertation
Defence Note: Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in Auditorium of the Medipolis (Kiviharjuntie 11), on May 27th, 2005, at 10 a.m.
Reviewer: Docent Kati Elima
Docent Marjo Kestilä


The role of sequence variations in genes encoding cartilage extracellular matrix (ECM) proteins were studied in osteoarthritis (OA) and multiple epiphyseal dysplasia (MED). The cartilage collagen genes COL2A1, COL9A1, COL9A2, COL9A3, COL11A1, and COL11A2 were screened for sequence variations in 72 Finnish probands and one US family with primary early-onset hip and/or knee OA. Altogether 239 sequence variations were found, of which 16 were not present in the controls. Seven of the unique variations — four in COL11A1, two in COL11A2, and one in COL2A1 — were studied further, because they resulted in the substitution of conserved amino acids or were predicted to affect mRNA splicing. Association analysis was performed by genotyping 6–12 common polymorphisms from each gene in 72 OA patients and 103 controls; no common predisposing alleles were identified. The results, however, suggest that mutations in the minor cartilage collagen genes can be the cause of OA in a subgroup of OA patients.

Two MED families with clinical and radiographic features suggestive of a collagen IX mutation were studied. Mutation screening of COL9A1, COL9A2, and COL9A3 yielded negative results. Instead, an R718W mutation in COMP was identified in both families. Clinical and radiographic overlap between patients with collagen IX mutations and patients with COMP mutations points to a common supramolecular complex pathogenesis.

Clinical, radiological and molecular analyses of known MED genes were performed on a cohort of 29 consecutive MED patients. The DTDST mutation was identified in four patients (14%), the COMP mutation in three (10%), and the MATN3 mutation in three (10%). Two new distinct phenotypic entities were identified in patients in whom no mutation was found. The findings suggest that mutations in the above mentioned known MED genes are not the major cause of MED and are responsible for less than half of the cases. The existence of additional MED loci is supported by the exclusion of known loci and finding of the specific subgroups among these patients.

The results suggest that genetic defects in ECM genes can predispose to OA and cause MED, even though the major genes involved in both disorders remain to be found.

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Series: Acta Universitatis Ouluensis. D, Medica
ISSN-E: 1796-2234
ISBN: 951-42-7733-3
ISBN Print: 951-42-7732-5
Issue: 832
Copyright information: © University of Oulu, 2005. This publication is copyrighted. You may download, display and print it for your own personal use. Commercial use is prohibited.