Osteogenesis imperfecta (OI: meaning imperfect bone formation) represents a heterogeneous group of disorders, the majority of which are the result of mutations that affect the structure and function of type I collagens. Most cases of OI are inherited as autosomal dominant diseases. Some individuals with type III OI inherited the disorder as an autosomal recessive trait. Most infants who have the severe forms of type II and type III OI acquired the disorder as a result of the appearance of a new mutation. Individuals with OI are characterized phenotypically with bone fragility and low bone mass. In addition, patients have soft tissue dysplasia, dentinogenesis imperfecta (abnormalities in the teeth), loss of hearing and alterations in the coloration of the sclera. Because of the heterogeneity of OI disorders, this syndrome has been divided into fifteen types with types I–IV being the result of mutations in specific collagen genes.
Type I OI is termed the mild type and is due to null mutations in the COL1A1 gene and results in bone fragility and blue sclera. In a patient with type I OI, the appearance of abnormal coloration of the sclera is most often seen upon ophthalmic examination. The bluish-gray coloration results from the thinning of the sclera due to loss of type I collagen deposition and a resultant ability to visualize the underlying choroid veins. The prevalence of type I OI is approximately 1 in 10,000 to 1 in 25,000. Diagnosis of type I OI is done by analysis of the production of type I procollagen in dermal fibroblasts in culture.
Type II OI is termed the perinatal lethal type and is due to mutations in the COL1A1 and COL1A2 genes. The mutations result in exon skipping and C-terminal proprotein mutants that interfere with collagen chain associations. Type II is characterized by severe bone fragility, absent calvarial mineralization and dark sclera. The frequency of type II OI is between 1 in 20,000 and 1 in 60,000. Affected infants are usually born premature and with low birth weight. Infants have characteristic facial features that include dark sclera, a beaked nose and an extremely soft calvarium. The outlook for type II OI patients is grim as this is a lethal disorder with life spans of only minutes to a few months. Death is usually the result of congestive heart failure, pulmonary insufficiency or infection.
Type III OI is referred to as the deforming type and is the result of exon skipping mutations in the COL1A1 and COL1A2 genes. The disorder is characterized by short stature, dentinogenesis imperfecta, light sclera and bone fragility leading to progressive deformities.
Type IV OI is called the mild deforming type and is the result of mutations in the COL1A1 and COL1A2 genes that result in exon skipping as well as the result of partial gene deletion mutants. The symptoms of type IV are similar to those of type III with individuals having mild short stature, dentinogenesis imperfecta and grayish sclera.
Type V OI is associated with moderate deformities with moderate to severe fragility of the long bones. Type V OI results from mutations in the gene (IFITM5) encoding interferon-induced transmembrane protein-5.
Type VI OI is a severe form of the disorder inherited as an autosomal recessive trait. Several patients who were originally classified as have the type IV form of the diseas were later shown to be harboring homozygous mutations in the serpin peptidase inhibitor, clade F, member 1 gene (symbol: SERPINF1). The serpins are serine protease inhibitors.
Type VII OI patients exhibit excessive post-translational modification of type I collagen resulting in delayed folding of the collagen helix. Patients with this form of OI were originally classified as OI type IIB individuals. Type VII OI results from mutations in the gene (CRTAP) encoding cartilage associated protein.
Type VIII OI is characterized by white sclerae, severe growth deficiency, extreme skeletal undermineralization, and bulbous metaphyses. This form of the disease is the result of mutations in the gene (P3H1) encoding prolyl 3-hydroxylase 1. This protein is also known as leucine- and proline-enriched proteoglycan 1 (LEPRE1).
Type IX OI is a fetal or neonatal lethal form of OI that results from mutations in the gene (PPIB) encoding peptidyl-prolyl isomerase B.
Type X OI is caused by mutations in the gene (SERPINH1) encoding serpin peptidase inhibitor, clade H, member 1. The SERPINH1 protein is a collagen-binding protein that functions as a chaperone in the endoplasmic reticulum.
Type XI OI is associated with dentinogenesis imperfecta as in the case of type III OI but is not due to mutations in either COL1A1 or COL1A2 gene. This form of OI was shown to be associated with mutations in the gene (FKBP10) encoding FK506-binding protein 10, also referred to as FKBP65 given that the protein has a mass of 65 kDa.
Type XII OI results from mutations in the gene (SP7) encoding the transcription factor, Sp7. Sp7 is a zinc-finger transcription factor that is a putatuve regulator of bone cell differentiation.
Type XIII OI is due to mutations in the gene (BMP1) encoding bone morphogenetic protein 1. The BMP1 protein is a metalloprotease that is capable of inducing cartillage formation.
Type XIV OI is the result of mutations in the gene (TMEM38B) encoding the protein, transmembrane protein 38B.
Type XV OI is due to mutation in the gene (WNT1) encoding the secreted glycoprotein growth factor called Wnt1.