Grant: Project Grant

Brittle bone disease, or osteogenesis imperfecta (OI), is a heritable disease that is mainly haracterized by bone fragility and short stature. In the large majority of patients, OI is caused by mutations in the two genes that encode collagen, the primary building block of bones. Other rare types of OI are caused by mutations in at least 10 other genes, all directly involved in the proper production and assembly of collagen. Two 'unique' types of OI are caused by mutation in a gene called BRIL (Bone-Restricted Ifitm-Like). The patients carrying such mutations in BRIL resemble other OI forms caused by collagen mutations with regard to many skeletal characteristics, such as fracture incidence, long-bone deformities, vertebral fractures and abnormal spine curvature. However, these 2 types have their own peculiar clinical and radiographic features not seen in other types of OI. The first shows uncontrolled bone masses growing on shafts of long bones like tibia and femurs, and fusion of the forearm bones. The second shows signs of bone that is very poorly mineralized. All patients identified have moderate to severe skeletal problems. However, it is still totally unknown how the mutant BRIL protein causes such variable and marked defects in the affected patients. The present project is aimed at elucidating some of these questions. We propose in part to characterize mouse models we have generated and which mimic symptoms observed in the patients. These will represent unique and valuable tools to study the mechanisms by which the mutant BRIL is detrimental to the skeleton. Furthermore, the outcome of our studies may be exploited to devise effective pharmacological treatments for OI, and be tested pre-clinically in the current mouse models.