Molecular analysis of type 1 collagen genes in inherited disorders.

The collagens are a family of related proteins which contain at least one triple-helical domain, a structure which is determined by the unique amino acid sequence of the polypeptide subunits. These proteins each have a specific function in the extracellullar matrices of connective tissues of multicellular organisms. In humans, type I collagen, the most abundant collagen type, is the major structural component of skin, tendon and bone. Mutations in the two genes encoding the subunits of type I collagen, COL1A1 and COL1A2, result in heterogeneous phenotypes. Some mutations result in osteogenesis imperfecta, the "brittle bone disorder", which itself has a wide range of phenotypes from mild to lethal in utero and others result in Ehlers-Danlos syndrome type VII, which is characterized by skin hyperextensibility and joint laxity. In this study, mutations were detected in these two genes using an adaptation of a recently-developed technique, single strand conformation polymorphism analysis, and DNA sequencing. Several silent changes in COL1A1 were identified and characterized. Two of these, an intronic HaeIII restriction fragment length polymorphism and an AciI polymorphism, are both of sufficient frequency to be potentially useful as markers in linkage analysis studies. The AciI polymorphism, resulting in substitution of an alanine residue with threonine, and a proline to alanine change were both found in normal individuals and therefore the altered amino acid residues do not appear to have any crucial role in the type I collagen molecule. Four patients with Ehlers-Danlos syndrome were studied but no mutations were identified. Several different mutations, assumed to result in the disorder, were found in coding sequences of COL1A1 or COL1A2 in patients with lethal and non-lethal forms of osteogenesis imperfecta. The discovery of these mutations has extended the knowledge of the relationship between the type and position of the mutation and the resulting phenotype.