OSTEOGENESIS IMPERFECTA AND TYPE-I COLLAGEN MUTATIONS - A LETHAL VARIANT CAUSED BY A GLY910-]ALA SUBSTITUTION IN THE ALPHA-1(I) CHAIN

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 heavily overmodified type-I collagen. The mutation introduced a local conformational perturbation. which causes abnormal exposure of arginine residues, the triple helical domain was susceptible to trypsin digestion even at 30-degrees-C. The chains bearing the point mutation were poorly secreted and short-term pulse experiments showed that the extensive intracellular retention of mutant trimers also impaired the secretion of normal chains. The molecular defect was localized in a COL1A1 allele by cloning and sequencing a cDNA region cor-responding 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 proalpha1(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.