Frameshift Mutation Near the 3 ' End of the COLIAl Gene of Type I Collagen Predicts an Elongated Proal ( 1 ) Chain and Results in Osteogenesis Imperfecta Type

Osteogenesis imperfecta (01) is a heterogeneous disorder of type I collagen of which OI type I, an autosomal dominant condition, is the mildest and most common form. Affected individuals have blue sclerae, normal stature, bone fragility without significant deformity and osteopenia. Fibroblasts from most affected individuals produce about half the expected amount of structurally normal type I collagen as a result of decreased synthesis of one of its constituent chains, proal(I), but the nature of the mutations which result in 01 type I are unknown. We describe a three generation family with OI type I in which all affected members have one normal COLlA1 allele and another from which the intragenic Eco RI restriction site near the 3' end of the gene is missing. Amplification by polymerase chain reaction and sequence determination of the normal allele and of the mutant allele in the domain that normally contains the Eco RI site demonstrated a 5-bp deletion frop the mutant allele. The deletion changes the translational readingframe beginning at the Eco RI site and predicts the synthesis of a proal(I) chain that extends 84 amino acids beyond the normal termination. Although the mutant proal(I) chain is synthesized in an in vitro translation system, we are unable to detect its presence in intact cells, suggesting that it is unstable and rapidly destroyed in one ofthe cell's degradative pathways. Our analysis of individuals with 01 type I from 20 families indicates that this is a unique mutation and suggests that the phenotype can result from multiple mechanisms that decrease the synthesis of normal type I procollagen molecules, including those that alter protein stability. (J. Clin. Invest. 1990. 85:282-290.) elongated proal(I) * frameshift OI type I