Studies of type I collagen in osteogenesis imperfecta

We used the results of skin fibroblast type I collagen analysis to improve the accuracy of diagnosis and genetic counseling for six patients with osteogenesis imperfecta. The fibroblasts of two patients with osteogenesis imperfecta type I synthesized a reduced quantity of qualitatively normal type I procollagen. Another patient with osteogenesis imperfecta type I had two populations of type I collagen molecules, one apparently normal and the other with a substitution of cysteine for glycine in the triple helical domain. Three sporadic cases with osteogenesis imperfecta types II, III, and IV were studied; in each proband a normal and an abnormal overmodified population of type I collagen molecules were demonstrated, and parental collagens were normal in the two available patients. These results indicated that the probands were heterozygous for new dominant mutations and assisted our genetic counseling, especially in osteogenesis imperfecta types II and III, which were formerly believed to be inherited in an autosomal recessive fashion. The results could not exclude parental germ line mosaicism for a new dominant mutation, which has resulted in recurrence in siblings of some patients with osteogenesis imperfecta, so prenatal diagnosis was therefore offered for future pregnancies. Analysis of chorionic villus cell collagen may facilitate antenatal diagnosis in selected cases, and the study of a larger number of patients may allow correlation of the biochemical defects with the natural history and prognosis.