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.

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.

Skull base abnormalities in osteogenesis imperfecta: a cephalometric evaluation of 54 patients and 108 control volunteers.

OBJECT: Osteogenesis imperfecta (OI), which usually results from mutations in type I collagen genes, causes bone fragility and deformities. The head is often abnormally shaped, and changes in skull base anatomy in the form of basilar impression and basilar invagination have been reported. The authors analyzed the skull base anatomy on standardized lateral cephalograms from 54 patients with OI (Types I, III, and IV) and 108 control volunteers. They were surprised to find that the previously used diagnostic measures for basilar abnormality in patients with OI were exceeded in 6.5 to 7.4% of the controls, and hence needed to be reevaluated. METHODS: The authors calculated the distance from the odontoid process to four reference lines, including a novel one, in the controls. The normal mean distances were exceeded by more than two standard deviations (SDs) in 28.3 to 35.2%, and by more than three SDs in 13.2 to 16.6% of the patients with OI. The latter figures reliably reflect the prevalence of basilar impression. As a sign of basilar invagination the odontoid process protruded into the foramen magnum or reached the foramen magnum level in 22.2% of the patients with OI, whereas none of the controls showed this feature. Platybasia (an anterior cranial base angle > 146 degrees) was present in 11.1% of the patients but in none of the controls. CONCLUSIONS: Platybasia, basilar impression, and basilar invagination were often coexpressed, but each was also present as an isolated abnormality. These three abnormalities and wormian bones were predominantly found in OI Types III and IV as well as in patients exhibiting dentinal abnormality.