Osteogenesis imperfecta and type-I collagen mutations. A lethal variant caused by a Gly910-->Ala substitution in the alpha 1 (I) chain.
Article Details
- CitationCopy to clipboard
Valli M, Sangalli A, Rossi A, Mottes M, Forlino A, Tenni R, Pignatti PF, Cetta G
Osteogenesis imperfecta and type-I collagen mutations. A lethal variant caused by a Gly910-->Ala substitution in the alpha 1 (I) chain.
Eur J Biochem. 1993 Feb 1;211(3):415-9.
- PubMed ID
- 7679635 [ View in PubMed]
- 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 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 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 pro alpha 1 (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.