CARBOHYDRATE DEFICIENT GLYCOPROTEIN SYNDROMES

碳水化合物缺乏糖蛋白综合症

• 批准号: 6177449
• 负责人: Hudson H. Freeze
• 金额: $ 34.05万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6177449
• 关键词: clinical research; diet therapy; enzyme deficiency; gene mutation; genetic mapping; glycoprotein biosynthesis; glycosylation; human subject; human therapy evaluation; inborn carbohydrate metabolism disorder; isoelectric point; mannose; mannose 6 phosphate isomerase; nutrition related tag; protein structure function; transferrin

Carbohydrate Deficient Glycoprotein Syndromes (CDGS) are genetic defects in N-glycosylation that cause severe neurological lesions and developmental delay. Two primary defects in CDGS are known, but many others are unknown. We propose to identify some of them by well- established and previously successful approaches. In addition, we discovered a non-neurological form of CDGS that presents with severe life- threatening protein-losing enteropathy, hypoglycemia, and intestinal bleeding. The primary defect is a 95% deficiency in phosphomannose isomerase (PMI, Fru-6< >Man-6-P). It is important to analyze additional patients with this type of CDGS since dietary mannose supplements effectively reverse all the clinical and biochemical anomalies. Ongoing Phase I studies of mannose therapy cover both neurological and gastrointestinal (PMI-deficient) patients. A simple isoelectric focusing test of serum transferrin is diagnostic for all types. To identify new defects and analyze additional PMI-deficient patients we plan to: 1. Analyze the structure of sugar chains on carbohydrate-deficient serum transferrin as an indicator of possible primary glycosylation defects. 2. Metabolically label patient fibroblasts with sugar precursor to assess protein glycosylation and all biosynthetic intermediates. 3.Based on results from im 2, directly assay biosynthetic enzymes likely to be deficient. If the defect occurs in known or highly conserved biosynthetic enzymes, identify the specific genetic lesions. 4. Identify mutations in PMI activity-deficient patients and relate these to their clinical conditions. These tried-and-true approaches have been highly successful for identify the defects of glycosylation mutants in man, mammalian cells and yeast. In fact, no second option is currently available. This is the first broad-based proposal to study CDGS defects, and by interfacing it with the mannose trials, it merges basic science and clinical medicine. As we learn more about these disorders and therapies, we expect to discover additional types of CDGS. Analysis of glycosylation-deficient patients will broaden our understanding ob both glycobiology and its immediate application to human glycosylation diseases.

碳水化合物缺乏糖蛋白综合征 (CDGS) 是 N-糖基化的遗传缺陷，会导致严重的神经损伤和发育迟缓。 CDGS 的两个主要缺陷是已知的，但许多其他缺陷尚不清楚。我们建议通过行之有效且以前成功的方法来识别其中一些。此外，我们还发现了一种非神经系统形式的 CDGS，其表现为严重危及生命的蛋白质丢失性肠病、低血糖和肠道出血。主要缺陷是磷酸甘露糖异构酶（PMI，Fru-6<>Man-6-P）95％缺乏。分析更多患有此类 CDGS 的患者非常重要，因为膳食甘露糖补充剂可以有效逆转所有临床和生化异常。正在进行的甘露糖治疗 I 期研究涵盖神经系统和胃肠道（PMI 缺乏）患者。血清转铁蛋白的简单等电聚焦测试可诊断所有类型。为了识别新的缺陷并分析其他 PMI 缺乏的患者，我们计划： 1. 分析碳水化合物缺乏的血清转铁蛋白上的糖链结构，作为可能的原发性糖基化缺陷的指标。 2. 用糖前体对患者成纤维细胞进行代谢标记，以评估蛋白质糖基化和所有生物合成中间体。 3.根据im 2的结果，直接测定可能缺乏的生物合成酶。如果缺陷发生在已知或高度保守的生物合成酶中，请识别特定的遗传损伤。 4. 识别 PMI 活性缺陷患者的突变，并将其与他们的临床状况联系起来。这些经过验证的方法在识别人类、哺乳动物细胞和酵母中糖基化突变体的缺陷方面非常成功。事实上，目前没有第二个选择。这是第一个研究 CDGS 缺陷的广泛提案，通过将其与甘露糖试验结合起来，它将基础科学和临床医学融为一体。随着我们对这些疾病和疗法的了解越来越多，我们期望发现其他类型的 CDGS。对糖基化缺陷患者的分析将拓宽我们对糖生物学及其在人类糖基化疾病中的直接应用的理解。