Y-position cysteine substitution in type I collagen (α1(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.

Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type

“…24,25 Two other pro␣1(I) R-to-C substitutions (R396C and R915C) were also associated with rupture of medium sized arteries, but affected individuals did not present EDS-like skin features. 25 Furthermore, a pro␣1(I)-R888C substitution was reported in a family presenting an EDS/osteogenesis imperfecta (OI) overlap phenotype, 26 and a pro␣1(I)-R836C was shown to be associated with autosomal-dominant Caffey disease. 27 …”

Osteogenesis imperfecta: Recent findings shed new light on this once well-understood condition

“…Mutations not involving the glycine residues within the triple helix of COL1 and mutations involving cysteine residues have been described in a subset of these patients. [17][18][19] It is also felt that the N-terminal mutations in COL1 result in abnormal protein folding, which leads to a milder OI/Ehlers Danlos Syndrome phenotype. 20 …”

Prolyl 3-Hydroxylase 1 Null Mice Display Abnormalities in Fibrillar Collagen-rich Tissues Such as Tendons, Skin, and Bones

“…The majority of these more recently described patients have been shown to have severe to lethal forms of autosomal recessive OI with some distinctive features (5)(6)10). The 3-hydroxylation of key residues in collagen I from these patients was significantly reduced indicating the importance of P3H1 and CRTAP in collagen stability, secretion, and ultimately in bone development.…”