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 Jagged 和 Delta 样家族的配体相互作用后被激活。 Notch 已被确定为一种信号通路，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发挥着关键作用。 Notch 受体及其配体的致病变异与多种具有显着颅面和骨骼表现的遗传性疾病有关。外侧脑膜膨出综合征 (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、骨骼发育异常和骨质流失。 LMS 与 NOTCH3 功能获得性致病变异相关。 LMS 实验小鼠模型表明，骨质流失是继发于破骨细胞生成增加的继发性，这是由于成骨细胞谱系细胞核因子 kappa B 配体的受体激活剂表达增强所致。 LMS 尚无有效疗法。针对 Notch3 的反义寡核苷酸和阻止 NOTCH3 激活的抗体正在该疾病的临床前模型中进行测试。总之，LMS 是一种与 NOTCH3 致病变异相关的严重遗传性疾病。新颖的实验模型提供了对致病机制和纠正疾病的方法的见解。