NEUROGLYCOPENIA: GENOTYPE-PHENOTYPE CORRELATION

神经血糖减少症：基因型-表型相关性

• 批准号: 6678316
• 负责人: DARRYL C DE VIVO
• 金额: $ 45.46万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6678316
• 关键词: Xenopus oocyte; apoptosis; biopsy; clinical research; developmental disease /disorder; developmental neurobiology; diazoxide; dietary carbohydrates; dietary lipid; dietary supplements; gene mutation; gene targeting; genetic polymorphism; genetically modified animals; genotype; glucagon; glucose tolerance test; glucose transporter; human subject; hyperglycemia; laboratory mouse; longitudinal human study; neuropathology; nutrition related tag; pathologic process; phenotype; point mutation; protein structure function; site directed mutagenesis

DESCRIPTION (provided by applicant): Glucose transporter protein Type I (Glut1), when deficient (GlutlDS, OMIM 606777), causes chronic neuroglycopenia and developmental encephalopathy. The deficiency results from GLUT1 haploinsufficiency, genetically transmitted as an autosomal dominant trait. The long-term objectives of this research project are improved understanding of the pathogenesis, increased awareness of the phenotypic presentations, and better treatment of the neurodevelopmental syndrome. Four specific aims are proposed to achieve these long-term objectives: (1) To expand our understanding of the GlutlDS phenotypes associated with GLUT1 gene mutations; (2) To correlate genotypic pathogenicity with phenotypic severity; (3) To replicate the human disease in an animal model; (4) To explore alternative treatment options for patients with GlutlDS. The research design and methods have been developed to increase recruitment of patients; to assess phenotypic variability by multi-disciplinary methods; and to serially evaluate patients over time to assess the phenotypic durability during development and the influences of gender on clinical expression. The phenotype will be correlated with the genotype by assessing the nature of the mutation and the kinetic and structure-function perturbations that result from these mutations. The Xenopus oocyte expression system is used to evaluate functional disturbances related to missense mutations. GLUT1 polymorphisms will be determined in the GlutlDS population and compared to the presence/absence of similar polymorphisms in a control population. A transgenic antisense mouse model and gene targeted homologous recombination knock-out mouse model will be examined clinically and neuropathologically for evidence of regional brain injury and neuronal apoptosis. Emphasis will be placed on establishing the cellular types most affected by the disease. Cellular dysfunction and apoptosis will be assessed by the in vitro study of neuronal and glial cultures derived from the mutant mouse models. Treatment opportunities will be explored in the mouse models and applied to the patient population assessing the relative benefits of a ketogenic diet and a carbohydrate diet, and the advantages of sustained hyperglycemia using uncooked cornstarch supplements and diazoxide. A 5-hour oral glucose tolerance test will be evaluated as a possible diagnostic tool measuring clinical, neuropsychological and electrographic changes associated with transient hyperglycemia.

描述（由申请人提供）：葡萄糖转运蛋白I型（GLUT1），当缺乏（glutlds，Omim 606777）时，会导致慢性神经糖浆症和发育性脑病。缺乏症是由GLUT1单倍弥平弥倍不足引起的，该疾病是作为常染色体显性特征传播的。该研究项目的长期目标是对发病机理的理解，提高了对表型表现的认识，并更好地治疗神经发育综合征。提出了四个具体目标来实现这些长期目标：（1）扩展我们对与Glut1基因突变相关的谷物表型的理解； （2）将基因型致病性与表型严重程度相关联； （3）在动物模型中复制人类疾病； （4）探索谷物患者的替代治疗选择。已经开发了研究设计和方法来增加患者的招募；通过多学科方法评估表型变异性；并随着时间的推移评估患者，以评估发育过程中的表型耐久性以及性别对临床表达的影响。表型将通过评估这些突变引起的突变的性质以及动力和结构功能扰动，与基因型相关。爪蟾卵母细胞表达系统用于评估与错义突变有关的功能障碍。 GLUT1多态性将在谷物群人群中确定，并将其与对照人群中相似的多态性存在相比。转基因反义小鼠模型和基因靶向同源重组小鼠模型将在临床和神经病理学上进行检查，以证明区域脑损伤和神经元细胞凋亡的证据。重点将放在建立受疾病影响最大的细胞类型上。细胞功能障碍和凋亡将通过对突变小鼠模型衍生的神经元和神经胶质培养物的体外研究进行评估。治疗机会将在小鼠模型中探索，并应用于评估生酮饮食和碳水化合物饮食的相对益处的患者群体，以及使用未煮过的玉米淀粉补充剂和二氮氧化物的持续高血糖的优势。 5小时的口服葡萄糖耐量测试将作为可能的诊断工具评估，该诊断工具测量了与瞬时高血糖相关的临床，神经心理学和电学变化。