Osteogenesis imprefecta and type‐I collagen mutations

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Abstract
In this study we describe a new dominant point mutation in COL1A1 causing a lethal form of Osteogenesis imperfecta (type II B). Dermal cultured fibroblasts from the proband were shown to produce both normal and hevily overmodified type‐I collagen. The mutation introduced a local conformational perturbation, which causes abonormal exposure of arginine residues; the triple helical domain was susceptible to trypsin digestion even at 30°C. The chains bearing the point mutationwere poorly secreted and short‐term pulse experiments showed that the extensive intracellular retention of mutant trimers also imparied the secretion of mormal chains.The molecular defect was localized in a COL1A1 allele by cloning and sequencing a cDNA region corresponding to the CB6 peptide. A G to C transversion which causes the substitution in the triple helical region of Gly910 with alanine was found. The mutation also causes the disappearance of a MspI‐recognition site at nucleotide 3263 of the proα1(I) coding sequence. Restriction analysis, along with the biochemical screening of collagens, allowed us to perform prenatal diagnosis on cells from chorionic‐villus sampling and to exclude the recurrence of the mutation in the sibling.

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