The molecular genetics of inherited connective tissue disorders.

The collagens are a family of structural proteins which function as an extracellular framework in eukaryotic organisms. They are characterised by a unique protein conformation which consists of three polypeptide chains in a triple helix. In vertebrates, at least thirteen collagen types encoded by at least twenty non-allelic genes have been identified. The collagen genes constitute a multi-gene family with a probable common evolutionary origin. Though generally dispersed, some of the genes are known to be clustered on certain chromosomes. Alterations in collagen genes can result in a heterogeneous group of heritable disorders of the connective tissues. There is accumulating evidence that similar phenotypes are due to similar mutations or location of mutations. One inherited disease of the connective tissues is the Marfan syndrome (MS). The genetic basis of this disease is still unknown. The four genes of the fibrillar collagens types I, II and III were chosen as candidate genes for a study of linkage in a large MS family. Three of these genes were excluded as being the mutant gene in this family. The heritable brittle bone disease, osteogenesis imperfecta (OI) is usually caused by mutations in either of the two genes for type I collagen. The technique of RNase A cleavage mapping was used to search for mutations in the a1 (I) gene in the lethal type of OI. The mutation in one individual was detected and mapped to exon 43 of the a1 (I) gene (COL1A1). The mutant gene was amplified, cloned and sequenced revealing a 9bp deletion from a repetitive region of one allele. It is surprising that such a mutation could produce OI in its most severe form. Studies to verify that the deletion is the disease-cause remain to be undertaken.