Notch (Notch1 through 4) are transmembrane receptors that determine cell differentiation and function, and are activated following interactions with ligands of the Jagged and Delta-like families. Notch has been established as a signaling pathway that plays a critical role in the differentiation and function of cells of the osteoblast and osteoclast lineages as well as in skeletal development and bone remodeling. Pathogenic variants of Notch receptors and their ligands are associated with a variety of genetic disorders presenting with significant craniofacial and skeletal manifestations. Lateral Meningocele Syndrome (LMS) is a rare genetic disorder characterized by neurological manifestations, meningoceles, skeletal developmental abnormalities and bone loss. LMS is associated with NOTCH3 gain-of-function pathogenic variants. Experimental mouse models of LMS revealed that the bone loss is secondary to increased osteoclastogenesis due to enhanced expression of receptor activator of nuclear factor kappa B ligand by cells of the osteoblast lineage. There are no effective therapies for LMS. Antisense oligonucleotides targeting Notch3 and antibodies that prevent the activation of NOTCH3 are being tested in preclinical models of the disease. In conclusion, LMS is a serious genetic disorder associated with NOTCH3 pathogenic variants. Novel experimental models have offered insight on mechanisms responsible and ways to correct the disease.

Notch（Notch1至4）是决定细胞分化和功能的跨膜受体，在与锯齿状和Delta状家族的配体相互作用后被激活。Notch已被确立为一种信号通路，在成骨细胞和破骨细胞谱系的细胞分化和功能以及骨骼发育和骨重塑中起关键作用。Notch受体及其配体的致病变体与各种遗传性疾病有关，这些疾病表现出明显的颅面和骨骼表现。外侧脑膜膨出综合症（LMS）是一种罕见的遗传性疾病，其特征是神经系统表现，脑膜膨出，骨骼发育异常和骨丢失。LMS与NOTCH3功能获得性致病变异有关。LMS的实验小鼠模型显示，由于成骨细胞谱系细胞增强了核因子κB配体的受体激活剂的表达，因此骨丢失是继破骨细胞形成增加的继发因素。LMS没有有效的疗法。靶向反义寡核苷酸缺口3在该疾病的临床前模型中正在测试能阻止NOTCH3活化的抗体和抗体。总之，LMS是与NOTCH3致病变异相关的严重遗传疾病。新颖的实验模型提供了有关引起疾病的机制和纠正方法的见识。