Golgi GDP-fucose transporter-deficient mice mimic congenital disorder of glycosylation IIc/leukocyte adhesion deficiency II
Golgi GDP-fucose transporter-deficient mice mimic congenital disorder of glycosylation IIc/leukocyte adhesion deficiency II
复制标题
DOI：
10.1074/jbc.m700314200
复制
发表时间：
2007-04-06
影响因子：
4.8
通讯作者：
Korner, Christian
中科院分区：
文献类型：
--
作者：
Hellbusch, Christina C.;Sperandio, Markus;Korner, Christian
糖蛋白的黏附修饰在自然界广泛存在。最近，单基因遗传性人类疾病“先天性糖基化失调IIc”（也称为“白细胞粘附缺陷II”）的发现强调了聚焦化的重要性。由于高尔基GDP聚焦转运蛋白（SLC35C1）活性缺陷，患者表现出糖蛋白低聚焦，临床上表现为智力和生长迟缓，持续的白细胞增多和严重的感染。为了研究不同器官中聚焦结构缺失所引起的影响，我们通过灭活高尔基体gdp转运蛋白基因（Slc35c1）建立了该疾病的小鼠模型。凝集素结合研究显示，Slc35c1（-/-）小鼠的组织和分离细胞中集中的糖缀合物显著减少。来自不同器官的细胞的聚焦处理导致糖蛋白聚焦状态的部分正常化，从而表明另一种GDP-聚焦运输机制。slc35c1缺陷小鼠表现出严重的生长迟缓、出生后死亡率升高、肺泡扩张和淋巴细胞减少。体外和体内白细胞粘附和滚动试验显示P-、E-和l -选择素配体功能严重受损。这些表型方面的多样性证明了聚焦化在哺乳动物有机体中的广泛影响。
Modification of glycoproteins by the attachment of fucose residues is widely distributed in nature. The importance of fucosylation has recently been underlined by identification of the monogenetic inherited human disease "congenital disorder of glycosylation IIc," also termed "leukocyte adhesion deficiency II." Due to defective Golgi GDP-fucose transporter ( SLC35C1) activity, patients show a hypofucosylation of glycoproteins and present clinically with mental and growth retardation, persistent leukocytosis, and severe infections. To investigate effects induced by the loss of fucosylated structures in different organs, we generated a mouse model for the disease by inactivating the Golgi GDP-transporter gene ( Slc35c1). Lectin binding studies revealed a tremendous reduction of fucosylated glycoconjugates in tissues and isolated cells from Slc35c1(-/-) mice. Fucose treatment of cells from different organs led to partial normalization of the fucosylation state of glycoproteins, thereby indicating an alternative GDP-fucose transport mechanism. Slc35c1-deficient mice presented with severe growth retardation, elevated postnatal mortality rate, dilatation of lung alveoles, and hypocellular lymph nodes. In vitro and in vivo leukocyte adhesion and rolling assays revealed a severe impairment of P-, E-, and L-selectin ligand function. The diversity of these phenotypic aspects demonstrates the broad general impact of fucosylation in the mammalian organism.