A NOTCH2 Mutation Causes Osteogenesis Imperfecta

项目摘要/摘要 Notch受体在细胞命运的决定和骨重建的调节中起着关键作用 直接或通过诱导其靶基因，即分裂毛发增强器(HES)和HES相关基因 YRPW主题(嘿)。一名2个月大的女婴携带NOTCH2致病变异(e4006G和gt；C) 外显子25导致骨骼中表皮生长因子(EGF)重复序列34的G1336R改变 脆弱和断裂。Notch信号的突变从来没有与成骨有关 不完美(OI)。鉴于关于Notch受体功能的重要知识已经产生在 骨骼，关于控制Notch激活的机制和依赖的机制，人们知之甚少 研究其胞外区与Notch配体的相互作用。我们创建了Notch24006G&gt；C小鼠模型 (Notch2em1Ecan)，在Notch2的25号外显子上存在4006G；C突变，并表现出细小而脆弱的骨骼 复制人类疾病的遗传和功能结果。这表明之前的一次 NOTCH2胞外区的未知突变会导致骨骼综合症；然而， 导致骨骼表现的机制尚未建立，将作为 拟开展的研究。我们的具体目标是：目的1)鉴定Notch2em1Ecan的骨骼表型 变种人。我们的目标是建立Notch2突变小鼠和 负责骨骼表型的机制；目的2)建立负责 Notch24006G&gt；C突变功能的变化。我们将确定NOTCH2突变体是否改变了亲和力 以及与锯齿状和Delta样家族的Notch配体的结合以及这是否会导致Notch的变化 Notch2em1Ecan突变体的激活和信号转导。被提议的工作的目标是理解小说 NOTCH2胞外区的功能及其相关疾病的骨骼表现 新发现的NOTCH2突变。

PROJECT SUMMARY/ABSTRACT Notch receptors play a critical role in cell fate decisions and in the regulation of bone remodeling, either directly or through the induction of their target genes, namely Hairy Enhancer of Split (HES) and Hes-related with YRPW motif (HEY). A 2 month old female child harboring a NOTCH2 pathogenic variant (e4006G>C) in exon 25 leading to a G1336R change in epidermal growth factor (EGF) repeat 34 presented with skeletal fragility and fractures. Never before has a mutation in Notch signaling been associated with osteogenesis imperfecta (OI). Whereas significant knowledge has been generated about the function of Notch receptors in the skeleton, little is known regarding mechanisms that control the activation of Notch and that are dependent on the interaction of its extracellular domain with Notch ligands. We created a Notch24006G>C mouse model (Notch2em1Ecan) that harbors a 4006G>C mutation in exon 25 of Notch2 and exhibits small and fragile bones replicating the genetic and functional outcomes of the human disorder. This reveals that a previously unrecognized mutation in the extracellular domain of NOTCH2 causes a skeletal syndrome; however, the mechanisms responsible for the skeletal manifestations are not established, and will be explored as part of the proposed research. Our specific aims are: Aim 1) To characterize the skeletal phenotype of Notch2em1Ecan mutants. Our goals are to establish the phenotype and cell lineage affected in Notch2 mutant mice and mechanisms responsible for the skeletal phenotype; Aim 2) To establish the mechanisms responsible for changes in Notch24006G>C mutant function. We will determine whether NOTCH2 mutants have altered affinity and binding to Notch ligands of the Jagged and Delta-like families and whether this results in changes in Notch activation and signaling in Notch2em1Ecan mutants. The goals of the proposed work are to understand novel functions of the NOTCH2 extracellular domain and the skeletal manifestations of diseases associated with a newly discovered NOTCH2 mutation.