Mild dominant osteogenesis imperfecta with intrafamilial variability: the cause is a serine for glycine α1(I) 901 substitution in a type-I collagen gene

Summary

The molecular defect responsible for a case of mild osteogenesis imperfecta (OI) with repeated femural fractures was investigated. The proband and his mother, who presented minor OI signs but no bone fractures, were shown to produce normal and abnormal type-I procollagen molecules in their dermal fibroblasts. The molecular defect was localized in about half of the proband's pro α1(I) mRNA molecules by chemical cleavage with piperidine of hydroxylamine-reacted mRNA ∶ cDNA heteroduplexes. The corresponding region was reversetranscribed and amplified by polymerase chain reaction (PCR). Cloning and sequencing of the amplified products revealed in both subjects a G-to-A transition in the first base of codon 901 of the α1(I) triple helical domain, which led to a serine for glycine substitution. Allele-specific oligonucleotide hybridization to amplified genomic DNA from fibroblasts and leukocytes confirmed the heterozygous nature of both patients and proved the absence of mosaicism. The presence of the mutation was excluded in other healthy family members, who were reported to have bluish sclerae. The mild phenotypic outcome of this newly characterized mutation contradicts previous findings on glycine substitutions in the C-terminal region of collagen triple helix, most of which caused lethal OI.