title: Local amino acid sequence patterns dominate the heterogeneous phenotype for the collagen connective tissue disease Osteogenesis Imperfecta resulting from Gly mutations.
abstract: Osteogenesis Imperfecta (OI), a hereditary connective tissue disease in collagen that arises from a single Gly → X mutation in the collagen chain, varies widely in phenotype from perinatal lethal to mild. It is unclear why there is such a large variation in the severity of the disease considering the repeating (Gly-X-Y)n sequence and the uniform rod-like structure of collagen. We systematically evaluate the effect of local (Gly-X-Y)n sequence around the mutation site on OI phenotype using integrated bio-statistical approaches, including odds ratio analysis and decision tree modeling. We show that different Gly → X mutations have different local sequence patterns that are correlated with lethal and nonlethal phenotypes providing a mechanism for understanding the sensitivity of local context in defining lethal and non-lethal OI. A number of important trends about which factors are related to OI phenotypes are revealed by the bio-statistical analyses; most striking is the complementary relationship between the placement of Pro residues and small residues and their correlation to OI phenotype. When Pro is present or small flexible residues are absent nearby a mutation site, the OI case tends to be lethal; when Pro is present or small flexible residues are absent further away from the mutation site, the OI case tends to be nonlethal. The analysis also reveals the dominant role of local sequence around mutation sites in the Major Ligand Binding Regions that are primarily responsible for collagen binding to its receptors and shows that non-lethal mutations are highly predicted by local sequence considerations alone whereas lethal mutations are not as easily predicted and may be a result of more complex interactions. Understanding the sequence determinants of OI mutations will enhance genetic counseling and help establish which steps in the collagen hierarchy to target for drug therapy.
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers University, 610 Taylor Road, Piscataway, NJ 08854, United States; State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
authors.forename: Jianxi
authors.initials: J
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
authors.forename: Zhangfu
authors.initials: Z
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
authors.forename: Xiuxia
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers University, 610 Taylor Road, Piscataway, NJ 08854, United States.
authors.forename: Rayna
authors.initials: R
authors.lastname: Addabbo
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers University, 610 Taylor Road, Piscataway, NJ 08854, United States. Electronic address: jean.baum@rutgers.edu.
authors.forename: Jean
authors.initials: J
authors.lastname: Baum
mesh_terms: D000595:Amino Acid Sequence; D024042:Collagen Type I / Q000737:chemistry / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D056726:Genetic Association Studies; D006801:Humans; D008958:Models, Molecular; D020125:Mutation, Missense; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D010641:Phenotype; D020539:Sequence Analysis, Protein
chemical_list: C000601279:COL1A2 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain
keywords: Bio-statistics; Collagen; Decision tree; Odds ratio; Osteogenesis Imperfecta