Arginine for glycine substitution in the triple-helical domain of the products of one alpha 2(I) collagen allele (COL1A2) produces the osteogenesis imperfecta type IV phenotype.
Skin fibroblasts from two affected members of a family with an autosomal dominant form of mild-moderate osteogenesis imperfecta produced two populations of type I collagen molecules. One population was normal and the other population contained alpha 2(I) chains which had a basic charge shift localized to a peptide from the carboxyl-terminal end of the triple-helical domain. The alpha chains in the abnormal molecules had increased post-translational modification along the entire triple-helical domain but the thermal stability was normal. We isolated a 28-kb BamHI fragment from the normal and mutant COL1A2 alleles from an affected family member. DNA sequence determination demonstrated that a single nucleotide change resulted in an arginine for glycine substitution at triple-helical position 1012, the last triple-helical glycine. These data demonstrate the stringent requirement for maintenance of the Gly-X-Y triplet sequence in type I collagen and suggest that point mutations which disrupt Gly-X-Y in alpha 2(I) produce milder clinical effects than similar mutations in alpha 1(I).
D000483:Alleles; D001120:Arginine; D003094:Collagen / Q000032:analysis / Q000235:genetics*; D004262:DNA Restriction Enzymes / Q000378:metabolism; D015245:Deoxyribonuclease BamHI; D005998:Glycine; D006801:Humans; D008875:Middle Aged; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D014176:Protein Biosynthesis
D003094:Collagen; D001120:Arginine; D004262:DNA Restriction Enzymes; D015245:Deoxyribonuclease BamHI; D005998:Glycine