Grant: Operating Grant

Brittle bone disease, or osteogenesis imperfecta (OI), is a heritable connective tissue disorder that is mainly characterized by bone fragility and often 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. Clinically, such patients are classified into OI types I to IV. Other rare types of OI (VI to XI) are caused by mutations in at least 6 other genes, all directly involved in the proper assembly of collagen fibers. OI type V (OI-V), is a bone fragility disorder resembling OI caused by collagen mutations with regard to many skeletal characteristics, such as fracture incidence, long-bone deformities, vertebral compression fractures and abnormal spine curvature. OI-V, however, has unique clinical and radiographic features not seen in other types of OI. They include uncontrolled bone masses growing on shafts of long bones like tibia and femurs, and fusion of the forearm bones. All patients identified with OI-V have a single mutation in the BRIL (Bone-Restricted Ifitm-Like) gene. The mutation causes the production of an abnormally long BRIL protein, which is believed to cause negative effects on the skeleton. 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 fully characterize animal (mouse) models we have generated and which should mimic symptoms observed in patients with OI-V. These will represent unique and valuable tools to study the mechanisms by which the mutant BRIL is detrimental to the skeleton. Biochemical and structural data gathered recently about BRIL and further exploited in the current study should be amenable to devise effective pharmacological treatments for OI-V, and be tested pre-clinically in the current mouse models.