GENETICS OF METHIONINE SYNTHASE IN HEALTH AND DISEASE

健康和疾病中的蛋氨酸合酶遗传学

• 批准号: 6290329
• 负责人: LAWRENCE BRODY
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6290329
• 关键词: blood vessel disorder; clinical research; enzyme activity; enzyme deficiency; gene mutation; genetic recombination; homocysteine; homocystinuria; human subject; human tissue; laboratory mouse; methionine; methyltransferase; model design /development

Vascular disease is the leading cause of death in the United States. Neural-tube defects are a major contributor to perinatal morbidity and mortality. Elevated levels of plasma homocysteine (a non-protein amino acid) have been found to correlate with an increased risk of NTDs and vascular disease. Methionine synthase (MS) catalyzes the vitamin B12 dependent, interconversion of homocysteine and 5-methyltetrahydrofolate to methionine and tetrahydrofolate. This is one of the few homocysteine consuming reactions in the body and reduced MS activity is predicted to lead to increased plasma homocysteine. We have cloned the human MS gene and demonstrated that hyperhomocysteinemia in a subset of patients is in fact due to mutations in the MS gene. Families with children affected with NTDs have been screened to determine if MS plays a role in NTD. We did notfind a connection between variants in MS and NTDs. We are now testing to see if the enzyme that acts with MS, MS-reductase plays a role in NTD. We also plan to asses avariety of candidate genes for a role in NTDs in a large collection of Irish NTD families (> 200 cases plus their unaffected parents). Rather than screening each gene for mutations, which is labor intensive and requires knowledge of the genomic structure of each gene, we are makers linked to the genes to test for association and/or transmission disequilibrium. Genes presently under study include methionine synthase (MS), methionine synthase reductase (MTRR), cystathionine-B-synthase (CBS), S-adenosyl- L-homocysteine hydrolase (SAHH), transcobalamin II (TCII), and methionine adenosyltransferase (MATa1). We will follow up any positive associations revealed by the polymorphic marker studies by screening the corresponding linked candidate genes with conventional mutation detection methods. In addition to the human genetic studies, we have used homologous recombination techniques to create a mouse model of MS deficiency. The phenotype of this mouse is currently being investigated. - spina bifida, infant mortality, pediatric research, genetics, heart disease - Human Subjects

在美国，血管疾病是导致死亡的主要原因。神经管缺陷是围产期发病率和死亡率的主要原因。已发现血浆同型半胱氨酸（一种非蛋白质氨基酸）水平升高与ntd和血管疾病风险增加有关。蛋氨酸合成酶（Methionine synthase， MS）催化依赖维生素B12的同型半胱氨酸和5-甲基四氢叶酸相互转化为蛋氨酸和四氢叶酸。这是体内为数不多的同型半胱氨酸消耗反应之一，MS活性降低预计会导致血浆同型半胱氨酸升高。我们已经克隆了人类多发性硬化症基因，并证明了一部分患者的高同型半胱氨酸血症实际上是由多发性硬化症基因突变引起的。对患有被忽视热带病儿童的家庭进行了筛查，以确定多发性硬化症是否在被忽视热带病中起作用。我们没有发现MS和NTDs变异之间的联系。我们现在正在测试与MS， MS还原酶一起作用的酶是否在NTD中起作用。我们还计划在大量爱尔兰NTD家族（约200例及其未受影响的父母）中评估各种候选基因在NTD中的作用。我们不是筛查每个基因的突变，这是劳动密集型的，需要了解每个基因的基因组结构，而是与基因联系起来的制造商，以测试关联和/或传递不平衡。目前正在研究的基因包括蛋氨酸合成酶（MS）、蛋氨酸合成酶还原酶（MTRR）、半胱硫氨酸- b合成酶（CBS）、s -腺苷- l-同型半胱氨酸水解酶（SAHH）、转钴胺素II （TCII）和蛋氨酸腺苷转移酶（MATa1）。我们将通过常规突变检测方法筛选相应的连锁候选基因，跟踪多态性标记研究显示的任何正相关。除了人类基因研究外，我们还使用同源重组技术创建了多发性硬化症小鼠模型。目前正在研究这只小鼠的表型。-脊柱裂，婴儿死亡率，儿科研究，遗传学，心脏病-人类受试者