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

 描述(申请人提供)：I型胶原不足或缺陷是成骨不全(OI)的原因，OI是一种遗传性疾病，其特征是骨骼发育异常，终身骨折风险增加。对一个表现为OI表型的家系进行外显子组测序，发现CREB3L1发生突变，编码碱性亮氨酸拉链(BZIP)转录因子。CREB3L1曾被报道与OI有关，但其发病机制尚不清楚。胶原蛋白相当大，它们从内质网(ER)运输到高尔基体包装并最终分泌是通过特殊的分泌机制实现的。CREB3L1是一种与CREB3L1密切相关的蛋白质，CREB3L2在调控软骨细胞中的一条这样的途径中发挥着作用，对正常的软骨形成非常重要。由于突变导致的CREB3L1功能受损可能扰乱成骨细胞中相同或相关的途径，并导致骨中I型胶原减少，这可以解释OI。也有证据表明，CREB3L1在细胞型的特定生理内质网应激途径中发挥作用，这可能与表型有关。先证者的成纤维细胞可用，但不表达CREB3L1。CREB3L1相关的OI将使用来自携带缺失基因的患者细胞的诱导多能干细胞(IPSC)来源的成骨细胞和携带家族突变的斑马鱼进行建模。这些模型将被用来寻找假想的分泌受损的证据，并确定CREB3L1在骨骼发育过程中的各种途径中的作用。这两个模型都将证实CREB3L1是OI疾病基因，并可能成为设计治疗脆性骨病的新药或治疗方法的工具。

 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.