New genes in bone development: what's new in osteogenesis imperfecta

Abstract

Osteogenesis imperfecta (OI) is a heritable bone dysplasia characterized by bone fragility and deformity and growth deficiency. Most cases of OI (classical types) have autosomal dominant inheritance and are caused by mutations in the type I collagen genes. During the past several years, a number of noncollagenous genes whose protein products interact with collagen have been identified as the cause(s) of rare forms of OI. This has led to a paradigm shift for OI as a collagen-related condition. The majority of the non-classical OI types have autosomal recessive inheritance and null mutations in their respective genes. The exception is a unique dominant defect in IFITM5, which encodes Bril and leads to hypertrophic callus and interosseous membrane ossification. Three recessive OI types arise from defects in any of the components of the collagen prolyl 3-hydroxylation complex (CRTAP, P3H1, CyPB), which modifies the collagen α1(I)Pro986 residue. Complex dysfunction leads to delayed folding of the procollagen triple helix and increased helical modification. Next, defects in collagen chaperones, HSP47 and FKBP65, lead to improper procollagen folding and deficient collagen cross-linking in matrix, respectively. A form of OI with a mineralization defect is caused by mutations in SERPINF1, whose protein product, PEDF, is a well-known antiangiogenesis factor. Defects in the C-propeptide cleavage enzyme, BMP1, also cause recessive OI. Additional genes, including SP7 and TMEM38B, have been implicated in recessive OI but are as yet unclassified. Elucidating the mechanistic pathways common to dominant and recessive OI may lead to novel therapeutic approaches to improve clinical manifestations.

Figure 1.

Defects in noncollagenous proteins causing OI have been identified. Top, Recessive OI is caused by defects in CRTAP, P3H1, and CyPB [forming the ER-resident, collagen prolyl 3-hydroxylation complex responsible for the modification of α1(I) proline 986], as well as HSP47 and FKBP65 (ER-resident collagen chaperones primarily involved in proline isomerization required for collagen helix folding). Bottom, Defects in IFITM5 (implicated in regulating mineralization), PEDF (a well-known inhibitor of angiogenesis), and BMP1 (responsible for procollagen C-propeptide cleavage) have recently been found to cause OI. HSP47, heat shock protein 47.