| Autor: |
Cabral, Wayne A., Makareeva, Elena, Letocha, Anne D., Scribanu, Nina, Fertala, Andrzej, Steplewski, Andrzej, Keene, Douglas R., Persikov, Anton V., Leikin, Sergey, Marini, Joan C. |
| Zdroj: |
Human Mutation; Apr2007, Vol. 28 Issue 4, p396-405, 10p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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