Department of Orthopaedic Surgery, the UConn Musculoskeletal Institute, UConn Health, Farmington, CT 06030, USA; Department of Medicine, the UConn Musculoskeletal Institute, UConn Health, Farmington, CT 06030, USA.
Metabolism. 2018 Mar;80:48-56. doi: 10.1016/j.metabol.2017.08.002. Epub 2017 Aug 24.
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.
In this article, current knowledge of Hajdu Cheney Syndrome (HCS) and related disorders is reviewed.
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.
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.
Notch 有四个跨膜受体，决定细胞的命运和功能。Notch 与其配体 Jagged 和 Delta-like 家族相互作用后被激活，导致 Notch 细胞内结构域（NICD）的切割和释放；这会转位到细胞核，诱导 Notch 靶基因的转录。 Notch 功能的缺失和获得性遗传疾病表现出严重的临床表现。
本文回顾了 Hajdu Cheney 综合征（HCS）和相关疾病的最新知识。
HCS 是一种罕见的遗传疾病，其特征是肢端骨溶解、骨折、身材矮小、神经表现、颅面发育异常、心血管缺陷和多囊肾。HCS 与 Notch2 获得性功能突变有关。该疾病的实验小鼠模型表明，骨丢失是由于核因子 kappa B 配体（Rankl）受体激活物表达增强导致破骨细胞生成和骨吸收增加所致。这表明抑制骨吸收可能对治疗与 HCS 相关的骨丢失有益。Notch2 是脾脏边缘区 B 细胞分配的决定因素，与 HCS 中发现的类似“体细胞”突变相关的边缘区 B 细胞淋巴瘤，但没有与 HCS 相关的淋巴瘤报告。
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 表现机制的深入了解。
