The genetics of folate and vitamin B12 metabolism relate

叶酸和维生素 B12 代谢的遗传学相关

• 批准号: 6988747
• 负责人: Lawrence C 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/6988747
• 关键词: congenital nervous system disorder; developmental genetics; developmental neurobiology; folate; genetic mapping; genetic polymorphism; human subject; neoplasm /cancer; neural plate /tube; patient oriented research; spina bifida; vitamin B12; vitamin metabolism

Research in the Molecular Pathogenesis is focused on defining changes in the genes that underlie inherited susceptibilities to common diseases such as cancer and birth defects. Changes in folate metabolism are correlated tumor formation and birth defects. Folate genes are also involved in the methylation of DNA and proper brain function. . We are searching for genetic variants in genes related to folate, methionine and homocysteine metabolism. Individuals affected with cancer or Spina Bifida (one form of neural tube defects) will be tested for these variants. Variants found at higher frequency in individuals with disease will help us identify genes associated with risk. In the past year we have tested more than 15 genes for variants that might perturb folate metabolism and therefore be associated with an increase risk of having a child with an neural tube defect. We found that variants in one of these genes, TC2, appear to affect the levels of vitamin B12 in the blood during pregnancy. This finding may be related to birth defects and also may help to explain why some elderly individuals become anemic and suffer neurological symptoms from vitamin B12 deficiency. We also found that mothers carrying a specific variant in a second gene, MTHFD1, have a 50% increased risk bearing a child with a neural tube defect. This previously un-described variant may be responsible for up to 25% of all neural tube defects. Approximately one in five individuals in the population carry one of these risk factors. We recently determined that this particular variant was also an risk factor for placental abruption a common cuase of miscarriage. We have re-created these genes in the laboratory and are currently using an experimental system to determine exactly how these variants alter the function of these proteins. A detailed knowledge of the function of these two genes will add to our understanding of neural tube defects and potentially help guide public health policy in the area of nutritional supplementation.

分子发病机理中的研究集中在定义基因的变化，这些基因是遗传性疾病（例如癌症和先天缺陷）的敏感性的基因的变化。叶酸代谢的变化是相关的肿瘤形成和先天缺陷。叶酸基因也参与了DNA的甲基化和适当的脑功能。 。我们正在寻找与叶酸，蛋氨酸和同型半胱氨酸代谢有关的基因中的遗传变异。将对患有癌症或脊柱裂（一种形式的神经管缺陷）的个体进行这些变体的测试。疾病个体中较高频率发现的变体将有助于我们识别与风险相关的基因。在过去的一年中，我们已经测试了可能扰动叶酸代谢的变体的15多个基因，因此与患有神经管缺陷的孩子的风险增加有关。我们发现，其中一种基因TC2中的一种变异似乎会影响怀孕期间血液中维生素B12的水平。这一发现可能与先天缺陷有关，也可能有助于解释为什么一些老年人贫血并遭受维生素B12缺乏症的神经系统症状。我们还发现，在第二个基因MTHFD1中携带特定变体的母亲的风险增加了50％，使儿童患有神经管缺陷。以前未描述的变体可能导致所有神经管缺陷的25％。人口中约有五分之一的人携带这些危险因素之一。我们最近确定，这种特殊的变体也是胎盘破裂的危险因素，这是流产的常见事件。我们已经在实验室重新创建了这些基因，目前正在使用实验系统来确定这些变体如何改变这些蛋白质的功能。详细了解这两个基因的功能将增加我们对神经管缺陷的理解，并有可能帮助指导补充营养的公共卫生政策。