title: Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans.
abstract: Osteogenesis imperfecta (OI) is a generalized disorder of connective tissue characterized by fragile bones and easy susceptibility to fracture. Most cases of OI are caused by mutations in type I collagen. We have identified and assembled structural mutations in type I collagen genes (COL1A1 and COL1A2, encoding the proalpha1(I) and proalpha2(I) chains, respectively) that result in OI. Quantitative defects causing type I OI were not included. Of these 832 independent mutations, 682 result in substitution for glycine residues in the triple helical domain of the encoded protein and 150 alter splice sites. Distinct genotype-phenotype relationships emerge for each chain. One-third of the mutations that result in glycine substitutions in alpha1(I) are lethal, especially when the substituting residues are charged or have a branched side chain. Substitutions in the first 200 residues are nonlethal and have variable outcome thereafter, unrelated to folding or helix stability domains. Two exclusively lethal regions (helix positions 691-823 and 910-964) align with major ligand binding regions (MLBRs), suggesting crucial interactions of collagen monomers or fibrils with integrins, matrix metalloproteinases (MMPs), fibronectin, and cartilage oligomeric matrix protein (COMP). Mutations in COL1A2 are predominantly nonlethal (80%). Lethal substitutions are located in eight regularly spaced clusters along the chain, supporting a regional model. The lethal regions align with proteoglycan binding sites along the fibril, suggesting a role in fibril-matrix interactions. Recurrences at the same site in alpha2(I) are generally concordant for outcome, unlike alpha1(I). Splice site mutations comprise 20% of helical mutations identified in OI patients, and may lead to exon skipping, intron inclusion, or the activation of cryptic splice sites. Splice site mutations in COL1A1 are rarely lethal; they often lead to frameshifts and the mild type I phenotype. In alpha2(I), lethal exon skipping events are located in the carboxyl half of the chain. Our data on genotype-phenotype relationships indicate that the two collagen chains play very different roles in matrix integrity and that phenotype depends on intracellular and extracellular events.
authors.affiliation: Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland 20892, USA. oidoc@helix.nih.gov
authors.forename: Joan C
authors.initials: JC
authors.lastname: Marini
authors.forename: Antonella
authors.initials: A
authors.lastname: Forlino
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Cabral
authors.forename: Aileen M
authors.initials: AM
authors.lastname: Barnes
authors.forename: James D
authors.initials: JD
authors.lastname: San Antonio
authors.forename: Sarah
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authors.lastname: Milgrom
authors.forename: James C
authors.initials: JC
authors.lastname: Hyland
authors.forename: Jarmo
authors.initials: J
authors.lastname: Körkkö
authors.forename: Darwin J
authors.initials: DJ
authors.lastname: Prockop
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.forename: Paul
authors.initials: P
authors.lastname: Coucke
authors.forename: Sofie
authors.initials: S
authors.lastname: Symoens
authors.forename: Francis H
authors.initials: FH
authors.lastname: Glorieux
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Roughley
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authors.initials: AM
authors.lastname: Lund
authors.forename: Kaija
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authors.lastname: Kuurila-Svahn
authors.forename: Heini
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authors.lastname: Hartikka
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cohn
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
authors.forename: Monica
authors.initials: M
authors.lastname: Mottes
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schwarze
authors.forename: Diana
authors.initials: D
authors.lastname: Chen
authors.forename: Kathleen
authors.initials: K
authors.lastname: Yang
authors.forename: Christine
authors.initials: C
authors.lastname: Kuslich
authors.forename: James
authors.initials: J
authors.lastname: Troendle
authors.forename: Raymond
authors.initials: R
authors.lastname: Dalgleish
authors.forename: Peter H
authors.initials: PH
authors.lastname: Byers
mesh_terms: D001665:Binding Sites; D003094:Collagen / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000235:genetics; D011509:Proteoglycans / Q000378:metabolism*
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D016023:Integrins; D011509:Proteoglycans; D003094:Collagen