Genotype Analysis for Diagnosis of Urea Cycle Disorders
尿素循环障碍诊断的基因型分析
基本信息
- 批准号:6935430
- 负责人:
- 金额:$ 9.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-07-15 至 2006-01-14
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): Urea Cycle Disorders (UCDs) are metabolic diseases disrupting ureagenesis. Unequivocal and rapid diagnosis of UCDs is difficult because hyperammonemia, the primary biochemical phenotype, is not specific to UCDs being observed in broad categories of metabolic deficiencies including fatty acid oxidation defects, lactic acidosis, and organic acidemias. Clinical presentation includes poor feeding, vomiting, and lethargy symptoms leading to misdiagnosis as sepsis. Differential diagnosis of individual urea cycle enzyme defects is complex. The urea cycle contains 6 core genes: N-acetylglutamate synthetase, carbamyl phosphate synthetase, ornithine transcarbamylase (OTC), argininosuccinate synthetase, argininosuccinate lyase, and arginase. OTC deficiency is the most frequently observed UCD and molecular genetic analysis is an established tool for diagnosis. Dye-Binding/High-Resolution Thermal Denaturation (DB/HRTD) is a chemistry that rapidly assesses a PCR product for sequence aberration and was first applied using a single sample instrument the HR-1. A prototype instrument, the LightScanner, allows DB/HRTD to be performed in 96 or 384 well plates enabling concurrent melting and analysis of all samples in a plate. Herein, it is proposed to demonstrate DB/HRTD as a simple means to rapidly assess the 6 core genes of the urea cycle. Specific Aim 1 seeks to validate a preliminary gene-scanning assay for the OTC gene. Specific Aim 2 proposes to design, develop, and provide preliminary validation of a gene-scanning assay for the N-acetylglutamate synthetase gene, defects in which cause NAGS deficiency. Specific Aim 3 proposes to use in situ analysis to unequivocally identify common polymorphisms by means of unlabeled probe chemistry within the context of gene scanning analysis. Specific Aim 4 will demonstrate gene scanning reagents (buffer, dye, dNTPs, oligonucleotides, enzyme) are stabilized by freeze drying and following re-suspension perform in a manner comparable to freshly prepared reagents. Rapid diagnosis of UCD is critical to patient survival. Genetic analysis for urea cycle defects is not widely available yet its utility as a component of the diagnostic regimen is recognized and documented. Stable freeze-dried reagents support rapid genotyping, to strengthen biochemical and clinical evidence in diagnosis of candidate patients. A plate-based system is compatible with block thermalcyclers and existing systems for automated plate loading.
描述(由申请人提供):尿素循环障碍(UCD)是破坏尿素生成的代谢性疾病。明确、快速诊断 UCD 很困难,因为高氨血症(主要生化表型)并不是在广泛类别的代谢缺陷(包括脂肪酸氧化缺陷、乳酸性酸中毒和有机酸血症)中观察到的 UCD 所特有的。临床表现包括喂养不良、呕吐和嗜睡症状,导致误诊为脓毒症。个别尿素循环酶缺陷的鉴别诊断很复杂。尿素循环包含6个核心基因:N-乙酰谷氨酸合成酶、氨甲酰磷酸合成酶、鸟氨酸转氨甲酰酶(OTC)、精氨基琥珀酸合成酶、精氨基琥珀酸裂合酶和精氨酸酶。 OTC 缺乏症是最常见的 UCD,分子遗传学分析是一种既定的诊断工具。染料结合/高分辨率热变性 (DB/HRTD) 是一种快速评估 PCR 产物序列畸变的化学方法,首次使用单样品仪器 HR-1 进行应用。 LightScanner 原型仪器允许在 96 或 384 孔板中执行 DB/HRTD,从而能够同时熔化和分析板中的所有样品。在此,建议证明 DB/HRTD 作为快速评估尿素循环 6 个核心基因的简单方法。具体目标 1 旨在验证 OTC 基因的初步基因扫描测定。具体目标 2 提议设计、开发 N-乙酰谷氨酸合成酶基因的基因扫描测定并提供初步验证,该基因的缺陷会导致 NAGS 缺陷。具体目标 3 建议使用原位分析,通过基因扫描分析背景下的未标记探针化学来明确识别常见的多态性。具体目标 4 将证明基因扫描试剂(缓冲液、染料、dNTP、寡核苷酸、酶)通过冷冻干燥实现稳定,并在重新悬浮后以与新鲜制备的试剂相当的方式运行。 UCD 的快速诊断对于患者的生存至关重要。尿素循环缺陷的遗传分析尚未广泛应用,但其作为诊断方案组成部分的实用性已得到认可和记录。稳定的冻干试剂支持快速基因分型,以加强候选患者诊断中的生化和临床证据。基于板的系统与块热循环仪和现有的自动板装载系统兼容。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Steven F Dobrowolski其他文献
Steven F Dobrowolski的其他文献
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