title: Predicting the clinical lethality of osteogenesis imperfecta from collagen glycine mutations.
abstract: Osteogenesis imperfecta (OI), or brittle bone disease, often results from missense mutation of one of the conserved glycine residues present in the repeating Gly-X-Y sequence characterizing the triple-helical region of type I collagen. A composite model was developed for predicting the clinical lethality resulting from glycine mutations in the alpha1 chain of type I collagen. The lethality of mutations in which bulky amino acids are substituted for glycine is predicted by their position relative to the N-terminal end of the triple helix. The effect of a Gly --> Ser mutation is modeled by the relative thermostability of the Gly-X-Y triplet on the carboxy side of the triplet containing the substitution. This model also predicts the lethality of Gly --> Ser and Gly --> Cys mutations in the alpha2 chain of type I collagen. The model was validated with an independent test set of six novel Gly --> Ser mutations. The hypothesis derived from the model of an asymmetric interaction between a Gly --> Ser mutation and its neighboring residues was tested experimentally using collagen-like peptides. Consistent with the prediction, a significant decrease in stability, calorimetric enthalpy, and folding time was observed for a peptide with a low-stability triplet C-terminal to the mutation compared to a similar peptide with the low-stability triplet on the N-terminal side. The computational and experimental results together relate the position-specific effects of Gly --> Ser mutations to the local structural stability of collagen and lend insight into the etiology of OI.
authors.affiliation: Genetics Department, School of Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Bodian
authors.forename: Balaraman
authors.initials: B
authors.lastname: Madhan
authors.forename: Barbara
authors.initials: B
authors.lastname: Brodsky
authors.forename: Teri E
authors.initials: TE
authors.lastname: Klein
mesh_terms: D019943:Amino Acid Substitution; D002942:Circular Dichroism; D024042:Collagen Type I / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000090602:Collagen Type I, alpha 1 Chain; D005998:Glycine / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D010013:Osteogenesis Imperfecta / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D005998:Glycine