Osteogenesis Imperfecta Type IV Biochemical Confirmation of Genetic Linkage to the proa 2 ( 1 ) Gene of Type I Collagen Richard

Fibroblasts from two affected members of a large pedigree in which osteogenesis imperfecta (01) type IV is genetically linked to the proa2(I) gene of type I collagen synthesize two populations of proa2(I) chains. One population is normal; the second population appears to have a deletion of about 10 amino acid residues from the middle of the triple helical domain. The mutation in proa2(I) causes increased posttranslational modification in the amino-terminal half of some proal(I) chains, lowers the melting temperature of type I collagen molecules that incorporate a mutant proa2(I) chain, and prevents or delays the secretion of those molecules from fibroblasts in cell culture. On the basis of this study and linkage studies in additional families, it appears that the 01 type IV phenotype is often the result of heterozygosity for mutations in proa2(I) that alter the triple helical structure of type I collagen.