CREB3L1 Is Necessary for Bone Development as Evidenced by Mutations that Cause Osteogenesis Imperfecta

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): Insufficiency or defectiveness of type I collagen is the cause of osteogenesis imperfect (OI), an inherited disorder characterized by abnormal bone development with an increased lifetime risk of fractures. Exome sequencing of a family presenting with OI phenotypes ranging from mild with few fractures to prenatal lethality revealed a mutation in CREB3L1, encoding a basic leucine zipper (bZIP) transcription factor. CREB3L1 has been reported once before in association with OI but the disease mechanism is still unclear. Collagen proteins are quite large and their transport from the endoplasmic reticulum (ER) to the Golgi for packaging and eventual secretion is achieved using specialized secretory machinery. A closely related protein to CREB3L1, CREB3L2, has a role in regulating one such pathway in chondrocytes and is important for proper cartilage formation. Impaired functionality of CREB3L1 due to mutation may perturb the same or a related pathway in osteoblasts and lead to reduced type I collagen in bone, explaining the OI. There is also evidence that CREB3L1 operates in cell-type specific physiological ER stress pathways that may contribute to the phenotype. Fibroblasts from the proband are available but do not express CREB3L1. CREB3L1-associated OI will be modeled using both induced pluripotent stem cell (iPSC)-derived osteoblasts from patient cells bearing the deletion and zebrafish engineered with the family mutation. These models will be used to look for evidence of the impaired secretion that is hypothesized and to define the role of CREB3L1 in various pathways that operate during bone development. Both models will serve as confirmation of CREB3L1 as an OI disease gene and potentially as tools for the design of new drugs or treatments for brittle bone disease.