Clinical and experimental aspects of notch receptor signaling: Hajdu-Cheney syndrome and related disorders
Clinical and experimental aspects of notch receptor signaling: Hajdu-Cheney syndrome and related disorders
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DOI：
10.1016/j.metabol.2017.08.002
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发表时间：
2018-03-01
影响因子：
9.8
通讯作者：
Canalis, Ernesto
中科院分区：
文献类型：
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作者：
Canalis, Ernesto
背景。有四种Notch跨膜受体决定细胞的命运和功能。Notch在与Jagged和Delta-like家族的配体相互作用后被激活，导致Notch细胞内结构域（NICD）的切割和释放；这易位到细胞核诱导Notch靶基因的转录。notch功能丧失和获得的遗传性疾病具有严重的临床表现。基本的程序。本文就Hajdu Cheney综合征（HCS）及相关疾病的最新知识进行综述。主要发现。HCS是一种罕见的遗传性疾病，其特征为肢端骨溶解、骨折、身材矮小、神经系统表现、颅面发育异常、心血管缺陷和多囊肾。HCS与NOTCH2功能获得突变相关。该疾病的实验小鼠模型显示，由于核因子κ B配体受体激活因子的表达增强，骨丢失是继发于破骨细胞生成和骨吸收增加的。这表明骨吸收抑制剂可能在治疗HCS相关的骨质流失中是有益的。Notch2是脾脏边缘区b细胞分配的决定因素，类似于HCS中发现的“体细胞”突变与边缘区b细胞淋巴瘤有关，但没有与HCS相关的淋巴瘤的报道。总之，HCS是一种与NOTCH2突变相关的严重遗传疾病。新的实验模型提供了对HCS表现的机制的见解。(C) 2017爱思唯尔公司版权所有。
Background. There are four Notch transmembrane receptors that determine the fate and function of cells. Notch is activated following its interactions with ligands of the Jagged and Delta-like families that lead to the cleavage and release of the Notch intracellular domain (NICD); this translocates to the nucleus to induce the transcription of Notch target genes. Genetic disorders of loss- and gain-of-NOTCH function present with severe clinical manifestations.Basic Procedures. In this article, current knowledge of Hajdu Cheney Syndrome (HCS) and related disorders is reviewed.Main Findings. HCS is a rare genetic disorder characterized by acroosteolysis, fractures, short stature, neurological manifestations, craniofacial developmental abnormalities, cardiovascular defects and polycystic kidneys. HCS is associated with NOTCH2 gain-of function mutations. An experimental mouse model of the disease revealed that the bone loss is secondary to increased osteoclastogenesis and bone resorption due to enhanced expression of receptor activator of nuclear factor kappa B ligand (Rankl). This would suggest that inhibitors of bone resorption might prove to be beneficial in the treatment of the bone loss associated with HCS. Notch2 is a determinant of B-cell allocation in the marginal zone of the spleen and "somatic" mutations analogous to those found in HCS are associated with B-cell lymphomas of the marginal zone, but there are no reports of lymphomas associated with HCS.Conclusion. In conclusion, HCS is a serious genetic disorder associated with NOTCH2 mutations. New experimental models have offered insight on mechanisms responsible for the manifestations of HCS. (C) 2017 Elsevier Inc. All rights reserved.