CTGT, Osteogenesis imperfecta, autosomal dominant (OI, types I, IIA, III & IV), COL1A1 & COL1A2

Collect at NMCP only Mon-Thursday by 1200

1215

Brittle bone disease

4 ml EDTA whole blood (purple top)

4 ml EDTA whole blood (purple top)

4°C

Osteogenesis imperfecta (OI), or brittle bone disease, is a heritable disorder of connective tissue characterized by bone fragility and low bone mass. OI is clinically and genetically heterogeneous with severity varying from mild to perinatal lethal. Mutations in the COL1A1 and COL1A2 genes cause approximately 90% of OI cases. COL1A1 and COL1A2 encode the alpha 1 and alpha 2 procollagen chains of type I collagen. Mutations in these genes cause autosomal dominant OI; OI types I (MIM 166200), II (MIM 166210), III (MIM 259420) and IV (MIM 166220). Mutations in the IFITM5 can also cause autosomal dominant OI, OI type V (MIM 610967). IFITM5 encodes interferon-induced transmembrane protein 5, also known as bone restricted ifitm-like protein, a molecule of unknown function. Mutations in eight genes have been linked to autosomal recessive OI or autosomal recessive OI-like disorders. One of these genes, SERPINF1, encodes pigment epithelium-derived factor (PEDF), a strong inhibitor of angiogenesis. PEDF is thought to function in bone formation and remodelling. Mutations in SERPINF1 cause OI type VI (MIM 613982). Mutations in the CRTAP, LEPRE1 and PPIB genes cause OI types VII (MIM 610682), VIII (MIM 610915) and IX (MIM 259440). These genes encode cartilage-associated protein, prolyl 3-hydroxylase 1 and cyclophilin B, components of a RER protein complex. This complex is involved in prolyl 3-hydroxylation of a single proline, P986, in the alpha 1 chains of type I procollagen. Cyclophilin B is a peptidyl-prolyl cis-trans isomerase that may catalyze the rate limiting step in collagen triple helix formation. Evidence indicates that this complex functions as a molecular chaperone and may also play an important role in the initial association of the C-terminal globular domains of the procollagen alpha chains. SERPINH1 encodes collagen-binding protein 2, also known as heat-shock protein 47 (HSP47). HSP47 is a molecule with known collagen binding properties and is considered to represent another procollagen chaperone. Mutations in SERPINH1 cause OI type X (MIM 613848). Mutations in FKBP10 cause OI type XI (MIM 610968), an OI type with distinctive histological findings. The product of FKBP10, FKBP65, is also localized to RER and has known collagen chaperone functions. Mutations in FKBP10 seem to result in decreased secretion of trimeric procollagen molecules. Interestingly, mutations in FKBP10 have also been reported to cause autosomal recessive Bruck syndrome, an OI-like disorder with associated contractures. The zinc finger transcription factor, SP7, is a putative master regulator of bone differentiation. A frameshift mutation in SP7 has been identified in a patient with OI type XII (MIM 613849). OI type XIII (MIM 614856) is caused by mutations in the bone morphogenetic protein 1 gene (BMP1). BMP1 is a metalloproteinase with activity directed against a number of molecules including type I procollagen C-terminal propeptide cleavage site.