New Congenital Disorders of Glycosylation: Therapy and Models

新的先天性糖基化疾病：治疗和模型

• 批准号: 9256465
• 负责人: Hudson H. Freeze
• 金额: $ 41.26万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256465
• 关键词: Affect; Alleles; Appearance; Basic Science; Biochemical; Biological Assay; Biological Markers; Blood Coagulation Disorders; Cell membrane; Cell model; Cells; Clinical; Complement; Complementary DNA; Complex; Congenital Disorders; DNA; Defect; Deformity; Development; Developmental Delay Disorders; Diagnosis; Disease; Dolichol; Engineering; Enzymes; FDA approved; Fibroblasts; Galactose; Galactose Metabolism Pathway; Genes; Goals; Golgi Apparatus; Hepatic; Human; Immunologics; Intellectual functioning disability; Intercellular adhesion molecule 1; Intestines; Investigation; Link; Mannose; Measures; Membrane Transport Proteins; Metabolism; Modeling; Molecular; Monitor; Monosaccharides; Muscular dystrophy cardiomyopathy; Mutation; N-Glycosylation Site; Pathologic; Patient Monitoring; Patients; Phenotype; Physicians; Physiological; Plasma; Polysaccharides; Production; Protein-Losing Enteropathies; Proteins; Publishing; Seizures; Serum; Site; TRAP Complex; Testing; Therapeutic Trials; Transferase; Transferrin; UDP-galactose transporter; Uridine Diphosphate Galactose; Work; Zebrafish; body system; clinical practice; design; exome sequencing; gene complementation; glycosylation; improved; knock-down; neurological pathology; novel; novel strategies; public health relevance; response; skeletal; stable isotope

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.

描述（由申请人提供）：许多患有糖基化先天性疾病（CDG）的患者在40个已知有缺陷的基因中没有突变。我们将在患者中识别7种新的CDG，并在其细胞中功能确认它们，并在斑马鱼中建模一些缺陷。一名患者正在进行简单的甘露糖疗法，我们将测试其他具有相同缺陷或缺陷的患者的细胞，以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体分离的UDP-半乳糖转运蛋白。候选有缺陷的基因将通过新开发的细胞生物标志物确认，以监测患者的糖基化低糖基化和通过cDNA互补或甘露糖疗法进行校正。先前使用两种斑马鱼模型的CDG模型表明，它们模仿了缺陷型表型，一种对甘露糖疗法的反应。我们的一组患者在两个寡核酸转移酶（OST）复合基因中已有Sanger确认的突变，其中两个在OST相关的TRAP复合基因中，在推定的甘露糖转运蛋白中，一种已知的UDP-gal Transporter，一个已知的UDP-gal transporter和一个假定的多乙醇代谢基因。令人惊讶的是，在已知的病理基因ALG1中，CDG病例的数量很高。这些患者成为意外的生物标志物聚糖。令人惊讶的是，甘露糖疗法减少了患者细胞或血清中该标志性聚糖的量，并似乎改善了患者的神经病学病理。其他患者可能会受益于无毒甘露糖疗法，大概是通过甘露糖转运蛋白分娩的。在AIM1中，我们将验证这些糖基化的新先天性疾病。在AIM 2中，选定的疾病将以斑马鱼形态进行建模，以进行表型和生化分析。 AIM 3将识别人类甘露糖优惠式转运蛋白和新型Golgi UDP-GAL转运蛋白。甘露糖和半乳糖疗法可用于斑马鱼模型以及这些患者。新的ALG1特异性血清生物标志物的戏剧性外观是基于非天然聚糖和识别可能对甘露糖治疗反应的患者的目标4。有证据表明，患有其他10例CDG缺陷的患者也可能对甘露糖疗法有反应。这强调了对其他患者进行简单疗法的紧迫性。完成该项目完成后，CDG患者和基础科学都将受益。