OSTEOGENESIS IMPERFECTA - MUTATIONS AND P HENOTYPES

Osteogenesis imperfecta (OI) is a heterogeneous group of inherited, mo stly dominant, disorders characterized by skeletal brittleness. OI gen erally results from mutations in the genes that encode the al(I) and a lpha 2(I) chains; these chains, associated in a triple helix constitut e type I collagen. Mutations leading to a purely quantitative defect r esult in discrete symptoms, compared to those resulting from mutations accompanied by an accumulation of mutated chains. These mutated subun its disturb the conformation of the triple helix and thus the function al properties of collagen fibrils, even in heterozygous patients. The severity of the phenotype depends on the nature of the mutated aminoac id and on its position in the protein; carboxyterminal mutations are u sually more severe than aminoterminal mutations, due to the fact that the folding of the constitutive triple helix always starts from the ca rboxyterminal end of the chains. Moreover, triple helix being composed of two alpha 1 chains and one alpha 2 chain, mutations in alpha 1 cha ins are generally more deleterious than those occuring in alpha 2 chai ns.