Minor cartilage collagens : characterization of the human COL9A1, COL9A2 and COL11A2 genes and the mouse Col11a2 gene. Identification of a mutation in the COL11A2 gene in a family with non-ocular Stickler syndrome

Vuoristo, Mirka (2003-12-05)
 
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Vuoristo, Mirka
University of Oulu
05.12.2003
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Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in the Auditorium L101 of the Department of Medical Biochemistry and Molecular Biology, on December 5th, 2003, at 1 p.m.
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Abstract

Collagens IX, a non-fibrillar collagen, and XI, a fibrillar collagen, are minor components of cartilage collagen fibrils, which form a supportive meshwork in the cartilage extracellular matrix (ECM). Collagens IX and XI are known to be present also in other tissues, including the vitreous body of the eye, the intervertebral disc, the inner ear, and various tissues during embryonic development. Collagen IX is suggested to act as a macromolecular bridge between collagen fibrils and other ECM molecules, and it may be important for the cohesive and compressive properties of cartilage, as well as the long-term stability of articular cartilage. Collagen XI is speculated to have a role in regulating the fibril diameter, and it may participate in interactions with other ECM components. However, the role of neither collagen IX nor XI has been confirmed yet.

As important but minor components of the cartilage ECM, collagens IX and XI are excellent candidates for relatively mild chondrodysplasias and even milder disease phenotypes involving cartilaginous tissues, such as non-syndromic hearing loss. There are in fact many reports describing defects in the genes for collagens IX and XI in patients with a variety of chondrodysplasias, including multiple epiphyseal dysplasia, Stickler syndrome, Marshall syndrome and otospondylomegaepiphyseal dysplasia. In order to screen the minor cartilage collagen genes for mutations, it is essential to know their gene structures. Therefore, the complete structures of the human COL9A1, COL9A2 and COL11A2 genes were characterized in this study. Also, to facilitate the analysis of the 5' region of the COL11A2 gene, the cDNA and partial genomic structure of the mouse Col11a2 gene were defined.

The information obtained in this study was utilized in the mutation analysis of a family with non-ocular Stickler syndrome. The COL11A2 gene was analyzed with conformation sensitive gel electrophoresis (CSGE) and sequencing, and a heterozygous single-nucleotide mutation causing a premature termination codon was found in the affected family members. Studying the effect of the mutation on the RNA revealed that the nonsense mutation caused the skipping of a 54-bp exon, presumably through a pathway called nonsense-associated altered splicing.

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