Y-position cysteine substitution in type I collagen (α1(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 α1(I)R888C (p.R1066C) substitution in one COL1A1 allele. Polyacrylamide gel electrophoresis (PAGE) of [3H]‐proline labeled steady‐state collagen reveals slight overmodification of the α1(I) monomer band, much less than expected for a substitution of a neighboring glycine residue, and a faint α1(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. Hum Mutat 28(4), 396–405, 2007. Published 2007 Wiley‐Liss, Inc.