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Predicting the clinical lethality of osteogenesis imperfecta from collagen glycine mutations.
Biochemistry. 2008 May 13; 47(19):5424-32.B

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+Show Affiliations

Genetics Department, School of Medicine, Stanford University, Stanford, California 94305, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18412368

Citation

Bodian, Dale L., et al. "Predicting the Clinical Lethality of Osteogenesis Imperfecta From Collagen Glycine Mutations." Biochemistry, vol. 47, no. 19, 2008, pp. 5424-32.
Bodian DL, Madhan B, Brodsky B, et al. Predicting the clinical lethality of osteogenesis imperfecta from collagen glycine mutations. Biochemistry. 2008;47(19):5424-32.
Bodian, D. L., Madhan, B., Brodsky, B., & Klein, T. E. (2008). Predicting the clinical lethality of osteogenesis imperfecta from collagen glycine mutations. Biochemistry, 47(19), 5424-32. https://doi.org/10.1021/bi800026k
Bodian DL, et al. Predicting the Clinical Lethality of Osteogenesis Imperfecta From Collagen Glycine Mutations. Biochemistry. 2008 May 13;47(19):5424-32. PubMed PMID: 18412368.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Predicting the clinical lethality of osteogenesis imperfecta from collagen glycine mutations. AU - Bodian,Dale L, AU - Madhan,Balaraman, AU - Brodsky,Barbara, AU - Klein,Teri E, Y1 - 2008/04/16/ PY - 2008/4/17/pubmed PY - 2008/6/11/medline PY - 2008/4/17/entrez SP - 5424 EP - 32 JF - Biochemistry JO - Biochemistry VL - 47 IS - 19 N2 - 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. SN - 1520-4995 UR - https://www.unboundmedicine.com/medline/citation/18412368/Predicting_the_clinical_lethality_of_osteogenesis_imperfecta_from_collagen_glycine_mutations_ L2 - https://doi.org/10.1021/bi800026k DB - PRIME DP - Unbound Medicine ER -