Glycine to tryptophan substitution in type I collagen in a patient with OItype III: a unique collagen mutation

We report a unique glycine substitution in type I collagen and highlight th e clinical and biochemical consequences. The proband is a 9 year old Turkis h boy with severely deforming osteogenesis imperfecta (OI). Biochemical ana lysis of (pro) collagen type I from a skin fibroblast culture showed both n ormal and over-modified alpha chains. Molecular analysis showed a G>T trans version in the COL1A2 gene, resulting in the substitution of glycine by try ptophan at position 277 of the alpha 2(I) collagen chain. Glycine substitut ions in type I collagen are the most frequent cause of the severe and letha l forms of OI. The phenotypic severity varies according to the nature and l ocalisation of the mutation. Substitutions of glycine by tryptophan, which is the most voluminous amino acid, have not yet been identified in type I c ollagen or any other fibrillar collagen. The severe, though nonlethal Or ph enotype associated with this mutation may appear surprising in view of the huge size of the tryptophan residue. The fact that the mutation resides wit hin a so called "non-lethal" region of the alpha 2(I) collagen chain suppor ts a regional model in phenotypic severity for alpha 2(I) collagen mutation s, in which the phenotype is determined primarily by the nature of the coll agen domain rather than the type of glycine substitution involved.