title: Y-position cysteine substitution in type I collagen (alpha1(I) R888C/p.R1066C) is associated with osteogenesis imperfecta/Ehlers-Danlos syndrome phenotype.
abstract: The most common mutations in type I collagen causing types II-IV osteogenesis imperfecta (OI) result in substitution for glycine in a Gly-Xaa-Yaa triplet by another amino acid. We delineated a Y-position substitution in a small pedigree with a combined OI/Ehlers-Danlos Syndrome (EDS) phenotype, characterized by moderately decreased DEXA z-score (-1.3 to -2.6), long bone fractures, and large-joint hyperextensibility. Affected individuals have an alpha1(I)R888C (p.R1066C) substitution in one COL1A1 allele. Polyacrylamide gel electrophoresis (PAGE) of [(3)H]-proline labeled steady-state collagen reveals slight overmodification of the alpha1(I) monomer band, much less than expected for a substitution of a neighboring glycine residue, and a faint alpha1(I) dimer. Dimers form in about 10% of proband type I collagen. Dimer formation is inefficient compared to a possible 25%, probably because the SH-side chains have less proximity in this Y-position than when substituting for a glycine. Theoretical stability calculations, differential scanning calorimetry (DSC) thermograms, and thermal denaturation curves showed only weak local destabilization from the Y-position substitution in one or two chains of a collagen helix, but greater destabilization is seen in collagen containing dimers. Y-position collagen dimers cause kinking of the helix, resulting in a register shift that is propagated the full length of the helix and causes resistance to procollagen processing by N-proteinase. Collagen containing the Y-position substitution is incorporated into matrix deposited in culture, including immaturely and maturely cross-linked fractions. In vivo, proband dermal fibrils have decreased density and increased diameter compared to controls, with occasional aggregate formation. This report on Y-position substitutions in type I collagen extends the range of phenotypes caused by nonglycine substitutions and shows that, similar to X- and Y-position substitutions in types II and III collagen, the phenotypes resulting from nonglycine substitutions in type I collagen are distinct from those caused by glycine substitutions.
authors.affiliation: Bone and Extracellular Matrix Branch, NICHD, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Cabral
authors.forename: Elena
authors.initials: E
authors.lastname: Makareeva
authors.forename: Anne D
authors.initials: AD
authors.lastname: Letocha
authors.forename: Nina
authors.initials: N
authors.lastname: Scribanu
authors.forename: Andrzej
authors.initials: A
authors.lastname: Fertala
authors.forename: Andrzej
authors.initials: A
authors.lastname: Steplewski
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Keene
authors.forename: Anton V
authors.initials: AV
authors.lastname: Persikov
authors.forename: Sergey
authors.initials: S
authors.lastname: Leikin
authors.forename: Joan C
authors.initials: JC
authors.lastname: Marini
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002478:Cells, Cultured; D002648:Child; D024042:Collagen Type I / Q000737:chemistry / Q000235:genetics* / Q000648:ultrastructure; D003545:Cysteine / Q000235:genetics; D019281:Dimerization; D004535:Ehlers-Danlos Syndrome / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D046529:Microscopy, Electron, Transmission; D020125:Mutation, Missense; D010013:Osteogenesis Imperfecta / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017434:Protein Structure, Tertiary; D020539:Sequence Analysis, Protein
chemical_list: D024042:Collagen Type I; D003545:Cysteine