FLMNB causes progressive skeletal fusions via TGF-Beta/BMP signaling modulation

 描述（由申请人提供）：轴骨和无骨骨骼的发育是一个严格调控的程序，导致高度雕刻的生物体。它依赖于多种分子途径和不同间充质衍生结构以及上覆上皮之间的相互作用。骨骼发育不良影响每1,250例妊娠中的1例，对骨骼发育不良的研究使我们有机会剖析控制这一高度复杂过程的分子和遗传机制。摘要脊椎腕跗骨结合是一种罕见的疾病，以脊椎、腕骨和跗骨的融合为特征。这种疾病是由细丝蛋白B（FLNB）无义突变的纯合性引起的。该基因编码一种蛋白质，该蛋白质充当肌动蛋白细胞骨架网络和从膜到细胞骨架的分子信号级联之间的支架。我推测在骨骼组织中FLNB在TGFβ/BMP信号传导中起衔接子的作用。我还假设FLNB的丢失影响软骨和骨周围组织的细胞命运，促进融合的发展。使用受影响的个体以及小鼠模型;我们正在研究这种疾病，以更好地了解FLNB的分子功能及其在软骨内骨骼形成中的作用，同时关注椎骨发育。此外，有些患者表现为SCT表型，但不携带FLNB突变。通过发现这一队列的潜在遗传原因，我们将确定更多参与脊椎发育和维持的基因。该项目的主要目的是利用人类表型和小鼠疾病模型来阐明参与脊椎发育和维持的分子机制。

 DESCRIPTION (provided by applicant): The development of both the axial and appendicular skeleton is a tightly regulated program leading to a highly sculpted organism. It is dependent on the interplay between multiple molecular pathways and differing mesenchymal derived structures as well as the overlying epithelium. The study of skeletal dysplasias, which affect 1 out of every 1,250 pregnancies, has given us the opportunity to dissect the molecular and genetic mechanisms that govern this highly complex process. Spondylocarpotarsal synostosis (SCT) is a rare disorder characterized by vertebral, carpal and tarsal bone fusions. This disorder results from homozygosity for nonsense mutations in Filamin B (FLNB). This gene encodes a protein that acts as a scaffold between the actin cytoskeleton network and molecular signaling cascades from the membrane to the cytoskeleton. I hypothesize that in skeletal tissues FLNB functions as an adaptor in TGFβ/BMP signaling. I also hypothesize that loss of FLNB influences the cell fate of tissues surrounding cartilage and bone promoting the development of fusions. Using both affected individuals as well as a mouse model; we are studying this disorder in order to gain a better understanding of the molecular function of FLNB and its role in endochondral skeletal formation while focusing on vertebral development. In addition, there are patients that phenocopy the SCT phenotype but do not harbor FLNB mutations. By discovering the underlying genetic cause of this cohort, we will identify more genes involved in vertebral development and maintenance. The central aim of this project is to use human phenotypes and mouse models of disease to elucidate the molecular mechanisms that participate in vertebral development and maintenance.