Osteogenesis imperfecta (OI) type I is characterized by bone fragility without 
significant deformity, osteopenia, normal stature, blue sclerae, and autosomal 
dominant inheritance. Dermal fibroblasts from most affected individuals produce 
about half the expected amount of type I collagen, suggesting that the OI type I 
phenotype results from a variety of mutations which alter the apparent 
expression of either COL1A1 or COL1A2, the genes encoding the chains of type I 
collagen. Short-pulse labeling of dermal fibroblasts with [3H]proline from 
affected individuals in 19 families indicates that most have alterations in the 
expected 2:1 synthetic ratio of pro alpha 1(I): pro alpha 2(I), with most having 
decreased production of pro alpha 1(I). Ratios of COL1A1:COL1A2 mRNA from these 
individuals, using slot-blot hybridization, indicate that they fall into 
different groups, but that most have decreased COL1A1 mRNA levels, compared with 
controls. These data suggest that most of our OI I families have COL1A1 
mutations. Copy number and size of the COL1A1 gene by restriction endonuclease 
analysis of genomic DNA from affected individuals are normal in the families 
examined. We have identified one 3 generation family in which all affected 
members have one normal COL1A1 allele and another with a 5 base-pair deletion 
near the 3' end of the gene. The deletion creates a shift in the translational 
reading-frame and predicts the synthesis of an elongated pro alpha 1(I) chain. 
In a second family, a father and a son have a single exon deletion that results 
from a splicing mutation. Chemical cleavage analysis of amplified cDNA from 
affected individuals in different regions of the COL1A1 gene, including the 
promoter, suggests that several individuals have point mutations within the 
coding region of the gene, while one individual may have a small deletion within 
the alpha 1(I) carboxyl-terminal propeptide region. Our data provide evidence 
for significant molecular heterogeneity within the OI type I phenotype and 
indicate that a variety of mutations can result in decreased synthesis of type I 
collagen.