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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
Author(s) -
Marini Joan C.,
Forlino Antonella,
Cabral Wayne A.,
Barnes Aileen M.,
San Antonio James D.,
Milgrom Sarah,
Hyland James C.,
Körkkö Jarmo,
Prockop Darwin J.,
De Paepe Anne,
Coucke Paul,
Symoens Sofie,
Glorieux Francis H.,
Roughley Peter J.,
Lund Alan M.,
KuurilaSvahn Kaija,
Hartikka Heini,
Cohn Daniel H.,
Krakow Deborah,
Mottes Monica,
Schwarze Ulrike,
Chen Diana,
Yang Kathleen,
Kuslich Christine,
Troendle James,
Dalgleish Raymond,
Byers Peter H.
Publication year - 2007
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20429
Subject(s) - osteogenesis imperfecta , mutation , type i collagen , biology , integrin , cartilage oligomeric matrix protein , genetics , fibril , exon , fibronectin , matrix metalloproteinase , collagen helix , dentinogenesis imperfecta , microbiology and biotechnology , extracellular matrix , gene , triple helix , anatomy , medicine , pathology , endocrinology , receptor , alternative medicine , osteoarthritis
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 proα1(I) and proα2(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 α1(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 α2(I) are generally concordant for outcome, unlike α1(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 α2(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. Hum Mutat 28(3), 209–221, 2007. Published 2006 Wiley‐Liss, Inc.