Rare diseases of connective tissues affecting bone and/or cartilage.
The chondrodysplasias are an extremely diverse and complex group of rare genetic disorders, which affect the development of the skeleton. There are over 200 unique and well-characterised phenotypes, which range in severity from relatively mild to severe and lethal forms. They have an overall prevalence of at least 4 per 10,000 and this extrapolates to a minimum of 178,000 people in the 25 member states that suffer from chondrodysplasia.
Many of the individual skeletal dysplasia phenotypes have been grouped into ‘bone dysplasia families’ on the basis of similar clinical and radiographic features and it has been proposed that members of the same family will share a common disease pathophysiology. Therefore, as a group of heterogeneous diseases, the chondrodysplasias have a complex aetiology but are likely to share similar basic mechanisms of disease initiation, progression and end-stage pathology.
In this context the principle objective of the proposed project is to determine the molecular, cell and extracellular matrix pathology of a number of distinct chondrodysplasia phenotypes, which result from mutations in a variety of different gene products that are important for normal bone development. To achieve this objective we have developed a series of mouse models of chondrodysplasia that closely mimic the relevant human phenotype. We will use a multidisciplinary systems biology approach to determine the molecular mechanisms that underpin the pathophysiology of these distinct chondrodysplasias. From this approach we can expect to identify common disease mechanisms and learn general principles about genotype-phenotype correlations in chondrodysplasia phenotypes. These data will ultimately pave the way for developing common therapeutic strategies that might be targeted to a range of individual phenotypes.