Genotype-phenotype correlations in nonlethal osteogenesis imperfecta caused by mutations in the helical domain of collagen type I.

[dentinogenesis imperfecta]

Osteogenesis imperfecta (OI ) is a heritable disorder with bone fragility that is often associated with short stature , tooth abnormalities (dentinogenesis imperfecta ), and blue sclera . The most common mutations associated with OI result from the substitution for glycine by another amino acid in the triple helical domain of either the alpha 1 or the alpha 2 chain of collagen type I . In this study , we compared the results of genotype analysis and clinical examination in 161 OI patients (median age : 13 years ) who had glycine mutations in the triple helical domain of alpha 1 (I ) (n =67 ) or alpha 2 (I ) (n =94 ). Serine substitutions were the most frequently encountered type of mutation in both chains . Compared with patients with serine substitutions in alpha 2 (I ) (n =40 ), patients with serine substitutions in alpha 1 (I ) (n =42 ) on average were shorter (median height z-score -6 .0 vs -3 .4 ; P =0 .005 ), indicating that alpha 1 (I ) mutations cause a more severe phenotype . Height correlated with the location of the mutation in the alpha 2 (I ) chain but not in the alpha 1 (I ) chain . Patients with mutations affecting the first 120 amino acids at the amino-terminal end of the collagen type I triple helix had blue sclera but did not have dentinogenesis imperfecta . Among patients from different families sharing the same mutation , about 90 and 75 % were concordant for dentinogenesis imperfecta and blue sclera , respectively . These data should be useful to predict disease phenotype in newly diagnosed OI patients .