New Congenital Disorders of Glycosylation: Therapy and Models

新的先天性糖基化疾病：治疗和模型

基本信息

批准号：
8838780
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
项目类别：
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/8838780
关键词：
Affect Alleles Appearance Basic Science Biochemical Biological Assay Biological Markers Blood Coagulation Disorders Cardiomyopathies Cell membrane Cell model Cells Clinical 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 Health Hepatic Human Intellectual functioning disability Intercellular adhesion molecule 1 Intestines Investigation Link Mannose Measures Membrane Transport Proteins Metabolism Modeling Molecular Monitor Monosaccharides Muscular Dystrophies Mutation N-Glycosylation Site Patient Monitoring Patients Phenotype Physicians Plasma Polysaccharides Production Protein-Losing Enteropathies Proteins Publishing Seizures Serum Site TRAP Complex Testing Therapeutic Trials Transferase Transferrin UDP-galactose transporter Work Zebrafish base body system clinical practice design dolichyl-diphosphooligosaccharide - protein glycotransferase exome sequencing gene complementation glycosylation improved knock-down neurological pathology novel novel strategies response skeletal stable isotope

项目摘要

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）：许多患有先天性糖基化障碍 (CDG) 的患者在 40 种已知缺陷基因中没有突变。我们将在患者体内鉴定出 7 个新的 CDG，并在其细胞中对它们进行功能确认，并在斑马鱼中模拟一些缺陷。一名患者正在进行简单的甘露糖治疗，我们将测试其他患者的细胞，这些患者具有相同的缺陷或其他需要甘露糖的步骤存在缺陷，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位于高尔基体的 UDP-半乳糖转运蛋白。候选缺陷基因将通过新开发的细胞生物标志物进行确认，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。之前使用两种 CDG 斑马鱼模型的研究表明，它们模仿糖基化缺陷表型，其中一种对甘露糖治疗有反应。我们组的患者在两个寡糖基转移酶 (OST) 复合体基因、两个 OST 相关 TRAP 复合体基因、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多甘醇代谢基因中具有桑格确认的突变。令人惊讶的是，大量 CDG 病例的已知病理基因 ALG1 发生突变。这些患者会产生一种意想不到的生物标志物聚糖。引人注目的是，甘露糖疗法减少了患者细胞或血清中标记聚糖的含量，并且似乎改善了患者的神经病理学。其他患者可能受益于无毒甘露糖疗法，大概是通过甘露糖转运蛋白传递的。在 AIM1 中，我们将验证这些新的糖基化先天性疾病。在 AIM 2 中，将在斑马鱼形态中对选定的疾病进行建模，以进行表型和生化分析。 AIM 3 将识别人类甘露糖优先转运蛋白和新型高尔基体 UDP-半乳糖转运蛋白。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将 AIM 4 的重点放在非天然聚糖的基础上，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。这强调了对其他患者尝试简单疗法的紧迫性。该项目完成后，CDG 患者和基础科学都将受益。