Clinical manifestations range from severe cases with Everolimus perinatal lethality to asymptomatic individuals with mild predisposition to fractures, normal stature, and normal life.1 Overall, the incidence of the different types of OI

is approximately 1 in 15,000-20,000 births and most cases are due to autosomal dominant inheritance with mutations in COL1A1 or COL1A2 genes, which encode the α1 (I) and α2 (I) chains of type I collagen. 1 Type I collagen, the main structural protein of the extracellular matrix of bone, skin, and tendons, consists of two pro-α-1 chains and one pro-α-2 chain that interweave, forming a rigid triple helix. Each α chain contains N-(amino) and C-(carboxy) terminal propeptides and a central domain consisting of 338 repeats of Gly-XY, where X and Y exclude cysteine and tryptophan, and which often are, respectively, proline and hydroxyproline. Glycine,

as the smallest amino acid, is the only residue that can occupy the axial position of the triple helix, so that any change in a glycine residue will result in the disruption of the helical structure.2 and 3 Mutations in COL1A1 and selleck compound COL1A2 genes alter the structure or the amount of type I collagen, resulting in a skeletal phenotype that ranges from subclinical to lethal. 1 These patients exhibit qualitative and quantitative abnormalities in type I collagen due to the dominant negative effect of the mutation, as the mutant pro-α chains are incorporated into the type I procollagen molecules that also contain normal pro-α chains. As a rule, when there is substitution of glycine in the α1 chain, the phenotype will depend on the position of the substitution: C-terminal substitutions result in severe disease phenotype, and N-terminal substitutions yield milder phenotypes.4 and 5 Residues with large lateral chains or charged residues are highly disruptive of the triple structure, regardless of where they are located. Different phenotypes have been found with the same mutation.6 In a consortium created in 2007 to study OI-causing Atezolizumab price mutations in type I collagen genes, 1,832 independent mutations were identified; 682 resulted in the substitution of glycine residues in the

triple helix domain of the encoded protein, and 150 in splice sites.6 Based on clinical, radiographic, and skeletal findings, mode of inheritance, and molecular genetic analyses, new OI types have been identified since 2006 through exome sequencing. The present study aimed to review the classification of OI and to update new related genes. The PubMed and Online Mendelian Inheritance in Man (OMIM) databases were used.7 Due to considerable phenotypic variability, Sillence et al.8 and 9 developed a classification of OI subtypes based on clinical features and disease severity (Table 1): OI type I, mild, common, with blue sclera; OI type II, perinatal lethal form; OI type III, severe and progressively deforming, with normal sclera; and OI type IV, moderate severity with normal sclera.