University of Oulu

From rare syndromes to a common disease : mutations in minor cartilage collagen genes cause Marshall and Stickler syndromes and intervertebral disc disease

Saved in:
Author: Annunen, Susanna1
Organizations: 1University of Oulu, Faculty of Medicine, Department of Medical Biochemistry and Molecular Biology
Format: ebook
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.3 MB)
Persistent link:
Language: English
Published: 1999
Publish Date: 1999-10-13
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 the Auditorium of the Department of Medical Biochemistry, on December 3rd, 1999, at 12 noon.
Reviewer: Docent Jaakko Ignatius
Professor Markku Savolainen


Collagens IX and XI are quantitatively minor components of the collagen fibrils in cartilage. The spectrum of the phenotypes caused by mutations in the COL2A1 gene coding for collagen II, the main cartilage collagen, is relatively well defined, but there is little data on the phenotypes caused by collagen IX and XI mutations.

The structure of the human COL11A1 gene coding for the 1 chain of collagen XI was characterized here. It was found to consist of 68 exons and span 160 kb, excluding introns 1 and 4. Over 50 kb of new intronic sequences were defined. The exon-intron organization coding for the major triple helical domain was found to be identical to that of the human COL11A2 gene, which codes for the 2 chain of collagen XI.

The sensitivity of conformation sensitive gel electrophoresis (CSGE) for mutation detection was improved and tested with a large number of sequence variations in collagen genes. The sensitivity with the revised conditions was found to be close to 100%. In addition, CSGE was found to be a simple and practical method for analyzing large numbers of samples.

Fifteen mutations in the COL11A1 gene and eight in the COL2A1 gene were found by CSGE in patients with Marshall or Stickler syndrome. The genotypic-phenotypic comparison indicated that mutations leading to a premature translation termination codon in the COL2A1 gene resulted in Stickler syndrome and splicing mutations of 54 bp exons in the C terminal half of the COL11A1 gene resulted in Marshall syndrome. The other COL11A1 mutations caused phenotypes overlapping both syndromes.

In an analysis of the COL9A2 gene in 157 patients with intervertebral disc disease, six were found to have a tryptophan for glutamine substitution in the central collagenous domain of the collagen IX molecule. None of 174 control individuals had this substitution. The substitution cosegregated with the phenotype in the families studied, and linkage and linkage disequilibrium analyses supported the association of the locus and the disease with a joint lod score of over 11.

see all

Series: Acta Universitatis Ouluensis. D, Medica
ISSN-E: 1796-2234
ISBN: 951-42-5413-9
ISBN Print: 951-42-5412-0
Issue: 555
Copyright information: © University of Oulu, 1999. This publication is copyrighted. You may download, display and print it for your own personal use. Commercial use is prohibited.