Research on the basic defect of carbohydrate-deficient glycoprotein syndrome

碳水化合物缺乏糖蛋白综合征的基本缺陷研究

• 批准号: 08670887
• 负责人: OHNO Kousaku
• 金额: $ 1.41万
• 依托单位: Tottori University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08670887/
• 关键词: carbohydrate-deficient glycoprotein syndrome; disialotransferrion; asiolotransferrin; dehydrodolichol reductase; 糖蛋白; 糖鎖; 小胞体; ドリコール; 遺伝病; Carbohydrate-deficient

The carbohydrtae-deficient glycoprotein (CDG) syndrome is newly recongized genetic disorder characterize by apppearance of serum asialo-and disialo-transferrin. We have previously reported that the sugar chain attached to transferrin in the patients is structurally normal and a defect in asparagine N-linked sugar chain in one or two of the possible glycosylation sites.In this study we have analyzed metabolic pathways from precursors to lipid linked oligosaccharide. When CDG fibroblasts were loaded with [3H] glucosamine and analyzed lipid linked oligosaccharide intermediates, the intermediates in CDG fibroblasts were decreased without specific block. Then we have loaded [3H] mannose and analyzed lipid linked oligosaccharide intermediates. We could not find any metabokic block in this pathway. Finally we have loaded [3H] mevalonic acid and found a metabolic block in a step from dehydrodolicol to dolicol. We have concluded that appearance of glycoproteins lacking sugar chain may caused by a partial deficiency of dehydrodolicol reduction^<2)>.Prenatal diagnosis of CDG syndrome using carbohydrate-deficient glycoprotein in cordblood has been reported to be impossible, because carbohydrate-deficient glycooproteins appear after birth. To detect abnormal processing of intracellular glycoprotein, we have studied lysosomal enzyme proteins in cultures CDG fibroblasts. Although we could not find any abnormally glycosylated enzyme proteins, we have found an increase in alpha chain of beta hexosaminidase protein, suggesting abnormal processing of hexosaminidase protein^<3)>.

碳水化合物缺乏糖蛋白（CDG）综合征是一种新近发现的以血清无唾液酸转铁蛋白和二唾液酸转铁蛋白异常为特征的遗传性疾病。我们以前曾报道，在患者的转铁蛋白连接的糖链是结构正常的，在天冬酰胺N-连接的糖链中的一个或两个可能的糖基化位点的缺陷。当CDG成纤维细胞负载[3 H]葡糖胺并分析脂质连接的寡糖中间体时，CDG成纤维细胞中的中间体减少而没有特异性阻断。然后，我们加载了[3 H]甘露糖并分析了脂质连接的寡糖中间体。我们在该通路中未发现任何代谢阻断。最后，我们负载了[3 H]甲羟戊酸，并发现了从脱氢多萜醇到多萜醇的代谢阻断。我们的结论是，缺乏糖链的糖蛋白的出现可能是由于脱氢糖醇还原的部分缺陷^<2）>。据报道，利用脐带血中缺乏碳水化合物的糖蛋白对CDG综合征进行产前诊断是不可能的，因为缺乏碳水化合物的糖蛋白在出生后才出现。为了检测细胞内糖蛋白的异常加工，我们研究了培养CDG成纤维细胞中的溶酶体酶蛋白。虽然我们没有发现任何异常糖基化的酶蛋白，但我们发现β氨基己糖苷酶蛋白的α链增加，表明氨基己糖苷酶蛋白的异常加工^<3）>。

项目成果

K.Yamashita and K.Ohno: "Glycoprotein and Disease" Elsevier(Amsterdam), 445-445 (1996)

K.Yamashita 和 K.Ohno：“糖蛋白与疾病”Elsevier（阿姆斯特丹），445-445（1996）

S.Ichisaka, K.Ohno, I.Yuasa, E.Nanba, H.Sakuraba, Y.Suzuki: "Increased expression of beta-hexosaminidase alpha chain in cultured skin fibroblasts from patients with carbohydrate-deficient glycoprotein syndrome type I" Brain Dey. 20 (in press). (1998)

S.Ichisaka、K.Ohno、I.Yuasa、E.Nanba、H.Sakuraba、Y.Suzuki：“碳水化合物缺乏糖蛋白综合征 I 型患者培养的皮肤成纤维细胞中 β-己糖胺酶 α 链的表达增加” Brain Dey

T.Ohkura, K.Fukushima, A.Kurisaki, H.Sagami, K.Ogura, K.Ohno, S.Hara-Kuge, K.Yamashita: "A partial deficiency of dehydrodolichol reduction is a cause of carbohydrate-deficient glycoprotein syndrome type I" J.Biol.Chem.272. 6868-6875 (1997)

T.Ohkura、K.Fukushima、A.Kurisaki、H.Sagami、K.Ogura、K.Ohno、S.Hara-Kuge、K.Yamashita：“脱氢多羟基化合物减少的部分缺乏是碳水化合物缺乏糖蛋白综合征的原因

S.Ichisaka et al.: "Increased expression of β-hexosaminidase α chain in cultured skin fibroblas from patients with carbohydrate-deficient glycoprotein syndrome type I." Brain Dev. (in press).

S. Ichisaka 等人：“I 型碳水化合物缺乏糖蛋白综合征患者的培养皮肤成纤维细胞中 β-己糖胺酶 α 链的表达增加。”

S.Ichisaka et al.: "Increased expression of β-hexosaminidase α chain in cultured skinfibroblast from patients with carbohydrate-deficient glycoprotein syndrome type I." Brain Dev. (in press).

S. Ichisaka 等人：“I 型碳水化合物缺乏糖蛋白综合征患者的培养皮肤成纤维细胞中 β-己糖胺酶 α 链的表达增加。”