Molecular basis of heritable connective tissue disease.

The family of collagens represents a series of highly vulnerable gene-protein systems. This can be explained by the fact that both the folding of the pro alpha chains and the assembly of collagen monomers into fibrils highly depend on the principle of nucleated growth, in which every subunit of the system must have the correct structure. DNA analysis showed that over 90% of patients with OI have mutations in one of the two structural genes for type I procollagen, that many patients with severe chondrodysplasias apparently have mutations in the gene for type II procollagen, and that most patients with the potentially lethal type IV variant of Ehlers-Danlos syndrome have mutations in the gene for type III procollagen. The incidence of such genetic diseases varies from 1:100,000 births for lethal forms of OI to 1:25,000 births for mild forms (48). Mild chondrodysplasias such as the Stickler syndrome may have an incidence of 1:10,000 births. It is the subject of current investigation whether some mutations in the genes for type I, II, and III procollagen can also cause some of the common diseases of later onset, such as osteoporosis, osteoarthritis, or familial aneurysms. These genes have been demonstrated to be mutated in at least some subsets, and further analysis of the exceptionally large genes for most collagens is underway to resolve these questions. Rapid DNA analysis techniques, which are developed independently in several laboratories and in a concerted effort through the human genome project, will soon make it possible to screen a population for genetic defects and identify people at risk for developing connective tissue disease. As vulnerable as the collagen gene-protein system might be, the multimeric collagens may prove nevertheless to be accessible to gene therapy, as the suppression of defective alleles, e.g., through antisense strategies, may be much easier to accomplish than the gene augmentation necessary to correct other genetically determined diseases.