Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans - PubMed (original) (raw)
Review
doi: 10.1002/humu.20429.
Antonella Forlino, Wayne A Cabral, Aileen M Barnes, James D San Antonio, Sarah Milgrom, James C Hyland, Jarmo Körkkö, Darwin J Prockop, Anne De Paepe, Paul Coucke, Sofie Symoens, Francis H Glorieux, Peter J Roughley, Alan M Lund, Kaija Kuurila-Svahn, Heini Hartikka, Daniel H Cohn, Deborah Krakow, Monica Mottes, Ulrike Schwarze, Diana Chen, Kathleen Yang, Christine Kuslich, James Troendle, Raymond Dalgleish, Peter H Byers
Affiliations
- PMID: 17078022
- PMCID: PMC4144349
- DOI: 10.1002/humu.20429
Review
Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans
Joan C Marini et al. Hum Mutat. 2007 Mar.
Abstract
Osteogenesis imperfecta (OI) is a generalized disorder of connective tissue characterized by fragile bones and easy susceptibility to fracture. Most cases of OI are caused by mutations in type I collagen. We have identified and assembled structural mutations in type I collagen genes (COL1A1 and COL1A2, encoding the proalpha1(I) and proalpha2(I) chains, respectively) that result in OI. Quantitative defects causing type I OI were not included. Of these 832 independent mutations, 682 result in substitution for glycine residues in the triple helical domain of the encoded protein and 150 alter splice sites. Distinct genotype-phenotype relationships emerge for each chain. One-third of the mutations that result in glycine substitutions in alpha1(I) are lethal, especially when the substituting residues are charged or have a branched side chain. Substitutions in the first 200 residues are nonlethal and have variable outcome thereafter, unrelated to folding or helix stability domains. Two exclusively lethal regions (helix positions 691-823 and 910-964) align with major ligand binding regions (MLBRs), suggesting crucial interactions of collagen monomers or fibrils with integrins, matrix metalloproteinases (MMPs), fibronectin, and cartilage oligomeric matrix protein (COMP). Mutations in COL1A2 are predominantly nonlethal (80%). Lethal substitutions are located in eight regularly spaced clusters along the chain, supporting a regional model. The lethal regions align with proteoglycan binding sites along the fibril, suggesting a role in fibril-matrix interactions. Recurrences at the same site in alpha2(I) are generally concordant for outcome, unlike alpha1(I). Splice site mutations comprise 20% of helical mutations identified in OI patients, and may lead to exon skipping, intron inclusion, or the activation of cryptic splice sites. Splice site mutations in COL1A1 are rarely lethal; they often lead to frameshifts and the mild type I phenotype. In alpha2(I), lethal exon skipping events are located in the carboxyl half of the chain. Our data on genotype-phenotype relationships indicate that the two collagen chains play very different roles in matrix integrity and that phenotype depends on intracellular and extracellular events.
Figures
FIGURE 1
Distribution of the mutations along the α1(I) collagen chain. A: Glycine substitutions caused by single-nucleotide changes. B: Glycine mutations shown for each substituting amino acid, indicated to the right end of each line. The top line indicates the scale used based on residue in the triple-helical region. The vertical bars indicate the mutations. Each horizontal line represents an α1(I) chain. NL, nonlethal; L, lethal.
FIGURE 2
Distribution of the mutations along the α1(I) collagen chain. A: Glycine substitutions caused by single-nucleotide changes. B: Glycine mutations shown for each substituting amino acid, indicated to the right end of each line. The top line indicates the scale used based on residue number in the triple-helical region. The vertical bars indicate the mutations. Each horizontal line represents an α2(I) chain. NL, nonlethal; L, lethal.
FIGURE 3
Recurrences of mutations at the same glycine residue in α1(I) (A) and α2(I) (B) collagen chains.
FIGURE 4
Glycine substitution map of the last 600 C-terminal amino acids of the α1(I) chain. There are three stretches of seven glycines without known substitutions at positions 328–346, 418–436, and 805–820. The last two regions are included within MLBR2 and MLBR3. The vertical bars indicate the glycine substitutions. The bottom boxes represent MLBR2 and MLBR3. The numbers flanking the two boxes denote glycine residue positions in the α1(I) chain.
FIGURE 5
A: Regional model for the distribution of mutations along the α2(I) chain. The lethal mutations are located in eight regularly spaced clusters. Amino acid residues at the boundary of each domain are indicated. Scale bars mark each 100 amino acid along the helix. B: Localization of the lethal clusters of the mutations (white boxes) on a collagen fibril D-period model composed of five collagen molecules (horizontal lines) [Chapman, 1974]. The dotted boxes show the binding region on the type I collagen fibril of keratin sulfate (KSPG), keratan sulfate and heparan sulfate (KSPG/HSPG), and dermatan sulfate and chondroitin sulfate proteoglycans (DSPG/CSPG). The monomer-level binding site for decorin core protein (DC) and DSPG are also shown as white boxes overlapping, respectively, lethal cluster number 8 and lethal cluster number 7.
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