Collagen I is a member of the Collagen superfamily of proteins, the proteins most abundant in mammals, and an essential component of bones, teeth, skin and connective tissues including ligaments and tendons. COL1A1 and COL1A2 are the genes that code for the collagen I alpha chains, α1 and α2 respectively. Collagen I is a heterotrimer of these two alpha chains, formed of two α1 and one α2 chains. Diseases resulting from genetic mutations in COL1A1 and COL1A2, include osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS), however, mutations in these genes have not been implicated in the development of osteoarthritis (OA).
At MRC Harwell Institute, large-scale mutagenesis screens, including the Harwell Ageing Screen, have been used to identify novel models of disease and establish links between genes and diseases. The mutagenised mouse lines MP-107 and TM44 were identified in such screens, exhibiting early-onset mild bone abnormalities at the pelvis and elbow. These animals subsequently developed late-onset phenotypes including abnormal bone growth at the knee and OA.
Genetic mapping and sequencing revealed that MP-107 and TM44, contained mutations in Col1a2 and Col1a1 respectively, which correspond to the genes COL1A2 and COL1A1 in humans. The MP-107 mutation was a T to A transversion at position 4521226 of Chromosome 6 resulting in alternative splicing at exon 22 of Col1a2. The TM44 mutation was a C to T transition at position 94836670 of Chromosome 11 resulting in a premature stop codon in exon 31 of Col1a1.
Extensive phenotyping analysis revealed that the bone abnormalities observed in these lines are a result of an OI phenotype. Evidence of an EDS phenotype was also identified in the line MP-107, indicating that MP-107 is likely a model of Col-1 related overlap syndrome, a proposed EDS subtype exhibiting aspects of OI and EDS. Collagen I related changes to the joint tissues is likely the cause of the OA phenotypes. The project has the potential to enhance understanding of both the development of Col-1 related overlap syndrome and OA, and possible targets for therapy
