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Y-position cysteine substitution in type I collagen (alpha1(I) R888C/p.R1066C) is associated with osteogenesis imperfecta/Ehlers-Danlos syndrome phenotype.
Hum Mutat. 2007 Apr; 28(4):396-405.HM

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+Show Affiliations

Bone and Extracellular Matrix Branch, NICHD, NIH, Bethesda, Maryland 20892, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17206620

Citation

Cabral, Wayne A., et al. "Y-position Cysteine Substitution in Type I Collagen (alpha1(I) R888C/p.R1066C) Is Associated With Osteogenesis imperfecta/Ehlers-Danlos Syndrome Phenotype." Human Mutation, vol. 28, no. 4, 2007, pp. 396-405.
Cabral WA, Makareeva E, Letocha AD, et al. Y-position cysteine substitution in type I collagen (alpha1(I) R888C/p.R1066C) is associated with osteogenesis imperfecta/Ehlers-Danlos syndrome phenotype. Hum Mutat. 2007;28(4):396-405.
Cabral, W. A., Makareeva, E., Letocha, A. D., Scribanu, N., Fertala, A., Steplewski, A., Keene, D. R., Persikov, A. V., Leikin, S., & Marini, J. C. (2007). Y-position cysteine substitution in type I collagen (alpha1(I) R888C/p.R1066C) is associated with osteogenesis imperfecta/Ehlers-Danlos syndrome phenotype. Human Mutation, 28(4), 396-405.
Cabral WA, et al. Y-position Cysteine Substitution in Type I Collagen (alpha1(I) R888C/p.R1066C) Is Associated With Osteogenesis imperfecta/Ehlers-Danlos Syndrome Phenotype. Hum Mutat. 2007;28(4):396-405. PubMed PMID: 17206620.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Y-position cysteine substitution in type I collagen (alpha1(I) R888C/p.R1066C) is associated with osteogenesis imperfecta/Ehlers-Danlos syndrome phenotype. AU - Cabral,Wayne A, AU - Makareeva,Elena, AU - Letocha,Anne D, AU - Scribanu,Nina, AU - Fertala,Andrzej, AU - Steplewski,Andrzej, AU - Keene,Douglas R, AU - Persikov,Anton V, AU - Leikin,Sergey, AU - Marini,Joan C, PY - 2007/1/9/pubmed PY - 2007/6/22/medline PY - 2007/1/9/entrez SP - 396 EP - 405 JF - Human mutation JO - Hum Mutat VL - 28 IS - 4 N2 - 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. SN - 1098-1004 UR - https://www.unboundmedicine.com/medline/citation/17206620/Y_position_cysteine_substitution_in_type_I_collagen__alpha1_I__R888C/p_R1066C__is_associated_with_osteogenesis_imperfecta/Ehlers_Danlos_syndrome_phenotype_ L2 - https://doi.org/10.1002/humu.20456 DB - PRIME DP - Unbound Medicine ER -