New Congenital Disorders of Glycosylation: Therapy and Models

描述（由申请人提供）：许多患有先天性糖基化疾病（CDG）的患者在40个已知缺陷基因中没有突变。我们将在患者中鉴定7种新的CDGs，并在其细胞中进行功能确认，并在斑马鱼中建立一些缺陷模型。一名患者正在进行简单的甘露糖治疗，我们将在其他需要甘露糖的步骤中测试具有相同缺陷或缺陷的其他患者的细胞作为潜在的治疗方法。我们将鉴定甘露糖选择性质膜转运蛋白和高尔基定位的udp -半乳糖转运蛋白。候选缺陷基因将被新开发的细胞生物标志物确认，以监测患者的低糖基化并通过cDNA互补或甘露糖治疗进行纠正。先前使用两种斑马鱼CDG模型的工作表明，它们模拟糖基化缺陷表型，其中一种对甘露糖治疗有反应。我们的患者组在两个低聚糖转移酶（OST）复合物基因、两个OST相关的TRAP复合物基因、一个假定的甘露糖转运蛋白、一个已知的UDP-Gal转运蛋白和一个假定的醇代谢基因中都有sanger证实的突变。令人惊讶的是，大量的CDG病例在一种已知的病理基因ALG1中发生突变。这些患者产生了一种意想不到的生物标志物聚糖。引人注目的是，甘露糖治疗减少了患者细胞或血清中标记聚糖的数量，似乎改善了一位患者的神经病理学。其他患者可能受益于无毒性甘露糖治疗，可能通过甘露糖转运体输送。在AIM1中，我们将验证这些新的先天性糖基化疾病。在AIM 2中，选定的疾病将在斑马鱼突变体中建模，用于表型和生化分析。AIM 3将鉴定人类甘露糖优先转运蛋白和新型高尔基体UDP-Gal转运蛋白。甘露糖和半乳糖疗法可用于斑马鱼模型，也可能用于这些患者。一种新的alg1特异性血清生物标志物的引人注目的出现使AIM 4以非天然聚糖为基础，并识别可能对甘露糖治疗有反应的患者。有证据表明，患有其他10种CDG缺陷的患者也可能对甘露糖治疗有反应。这强调了在其他病人身上尝试一种简单疗法的紧迫性。当这个项目完成后，CDG患者和基础科学都将受益。

DESCRIPTION (provided by applicant): Many patients with Congenital Disorders of Glycosylation (CDG) do not have mutations in the 40 known defective genes. We will identify 7 new CDGs in patients and functionally confirm them in their cells and model some defects in zebrafish. Simple mannose therapy is ongoing in one patient and we will test cells from other patients with the same defect or defects in other mannose-requiring steps as a potential treatment. We will identify mannose-selective plasma membrane transporters and Golgi-located UDP-Galactose transporters. Candidate defective genes will be confirmed with newly developed cellular biomarkers to monitor patients' hypo-glycosylation and correction with cDNA complementation or mannose therapy. Previous work using two zebrafish models of CDG show they mimic glycosylation-deficient phenotypes and one responds to mannose therapy. Our group of patients has Sanger-confirmed mutations in two oligosaccharyl-transferase (OST) complex genes, two in the OST-associated TRAP complex genes, in a putative mannose transporter, a known UDP-Gal transporter, and a putative dolichol metabolism gene. A surprisingly high number of CDG cases have mutations in a known pathological gene, ALG1. These patients make an unanticipated biomarker glycan. Strikingly, mannose therapy reduces the amount of that marker glycan in patient cells or serum and appears to improve one patient's neurological pathology. Other patients may benefit from non-toxic mannose therapy, presumably delivered through mannose transporter(s). In AIM1 we will verify these new Congenital Disorders of Glycosylation. In AIM 2, selected disorders will be modeled in zebrafish morphants for phenotypic and biochemical analysis. AIM 3 will identify human Mannose- preferential transporter(s) and novel Golgi UDP-Gal Transporters. Mannose and galactose therapies may be used in the zebrafish models and possibly in these patients. The dramatic appearance of a new ALG1-specific serum biomarker focuses AIM 4 on the basis of non-natural glycan and identifying patients who might respond to mannose therapy. Evidence suggests that patients with 10 other CDG defects may also respond to mannose therapy. This emphasizes the urgency of trying a simple therapy on other patients. Both CDG patients and basic science will benefit when this project is completed.