Osteogenesis Imperfecta

Published on 22/03/2015 by admin

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Chapter 692 Osteogenesis Imperfecta

Osteoporosis, a feature of both inherited and acquired disorders, classically demonstrates fragility of the skeletal system and a susceptibility to fractures of the long bones or vertebral compressions from mild or inconsequential trauma. Osteogenesis imperfecta (OI) (brittle bone disease), the most common genetic cause of osteoporosis, is a generalized disorder of connective tissue. The spectrum of OI is extremely broad, ranging from forms that are lethal in the perinatal period to a mild form in which the diagnosis may be equivocal in an adult.


Type I collagen is a heterotrimer composed of two α1(I) chains and one α2(I) chain. The chains are synthesized as procollagen molecules with short globular extensions on both ends of the central helical domain. The helical domain is composed of uninterrupted repeats of the sequence Gly-X-Y, where Gly is glycine, X is often proline, and Y is often hydroxyproline. The presence of glycine at every 3rd residue is crucial to helix formation because its small side chain can be accommodated in the interior of the helix. The chains are assembled at their carboxyl ends; helix formation then proceeds linearly in a carboxyl to amino direction. Concomitant with helix assembly and formation, helical proline and lysine residues are hydroxylated by prolyl 4-hydroxylase and lysyl hydroxylase and some hydroxylysine residues are glycosylated.

Collagen structural defects are predominantly of two types: 80% are point mutations causing substitutions of helical glycine residues or crucial residues in the C-propeptide by other amino acids, and 20% are single exon splicing defects. The clinically mild OI type I has a quantitative defect, with null mutations in one α1(I) allele leading to a reduced amount of normal collagen.

The glycine substitutions in the two α chains have distinct genotype-phenotype relationships. One third of mutations in the α1 chain are lethal, and those in α2(I) are predominantly nonlethal. Two lethal regions in α1(I) align with major ligand binding regions of the collagen helix. Lethal mutations in α2(I) occur in 8 regularly spaced clusters along the chain that align with binding regions for matrix proteoglycans in the collagen fibril.

Classic OI is an autosomal dominant disorder. Some familial recurrences of OI are caused by parental mosaicism for dominant collagen mutations. Recessive OI (types VII and VIII) accounts for 5-7% of new OI in North America. These types are caused by null mutations in the genes coding for two of the components of the collagen prolyl 3-hydroxylation complex in the endoplasmic reticulum, LEPRE1, which encodes P3H1, or CRTAP. This complex is responsible for post-translational modification of a single proline residue, P986, on the α1(I) chains. It is not yet clear whether absence of the complex or the modification is the crucial feature of recessive OI.