Y-position cysteine substitution in type I collagen (alpha1(I) R888C/p.R1066C) is associated with osteogenesis imperfecta/Ehlers-Danlos syndrome phenotype.
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.
Cabral
Wayne A
WA
Bone and Extracellular Matrix Branch, NICHD, NIH, Bethesda, Maryland 20892, USA.
Makareeva
Elena
E
Letocha
Anne D
AD
Scribanu
Nina
N
Fertala
Andrzej
A
Steplewski
Andrzej
A
Keene
Douglas R
DR
Persikov
Anton V
AV
Leikin
Sergey
S
Marini
Joan C
JC
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
D024042:Collagen Type I; D003545:Cysteine