Folic Acid, Parental Mutation Rates and the Risk for Neural Tube Defects

 描述（由申请人提供）：出生缺陷是主要的儿科医疗保健问题之一，但几乎没有预防策略，尽管食品供应中添加了叶酸，但美国出生缺陷的患病率几十年来一直保持相对稳定。神经管缺陷（NTD）是所有出生缺陷中最常见和最严重的，影响每1,000名美国新生儿中0.5-1名，但其复杂的病因学仍知之甚少（Wallingford et al.，2013年）。众所周知，孕前补充叶酸可以降低NTD的风险，但这种有益作用的潜在机制尚不清楚。大约30%的NTD不能通过母亲围受孕期补充叶酸来预防。我们的初步数据表明，平面细胞极性（PCP）途径的罕见突变可增加NTDs的风险，而致突变物，如多环芳烃富集在NTDs胎儿/婴儿的胎盘。我们假设NTD是由罕见的多种突变的组合引起的。较高的突变率导致较高的NTDs患病率。叶酸可能通过降低突变率来预防NTDs。此外，我们假设父亲补充叶酸可以进一步降低NTD率。我们有一个独特的机会来评估叶酸补充剂对突变率的影响，通过利用以前收集的来自几个不同队列的NTD患者和对照的生物样本。此外，我们建议使用小鼠模型，以更好地了解叶酸和体内突变率之间的关系。这项研究的结果将解释叶酸如何预防NTD，并将揭示干预叶酸耐药NTD的新途径。因此，拟议研究的成功完成可能会对我们理解影响全球约6%出生的疾病产生重大影响，并构成社会最年轻成员的主要医疗保健问题之一。

 DESCRIPTION (provided by applicant): Birth defects are among the leading pediatric healthcare issues, yet there are few prevention strategies and the prevalence of birth defects in the US has remained relatively stable for decades, despite folic acid fortification of the food supply. Neural tube defects (NTDs) are among the most common and serious of all birth defects affecting 0.5-1 per 1,000 US newborns, yet their complex etiology remains poorly understood (Wallingford et al., 2013). It is well established that pre-pregnancy supplementation with folic acid can reduce the risk of NTDs, but the underlying mechanism of this beneficial effect is unclear. Approximately 30% of NTDs cannot be prevented by maternal periconceptional folate supplementation. Our preliminary data showed that rare mutations in planar cell polarity (PCP) pathway could increase the risk of NTDs, while mutagens such as polycyclic aromatic hydrocarbons were enriched in the placentas of NTDs fetuses/infants. We hypothesized that NTDs are caused by combinations of rare multiple mutations. Higher mutation rates results in a higher NTDs prevalence. It is possible that folic acid can prevent NTDs by reducing the mutation rate. Furthermore, we hypothesize that paternal supplementation with folic acid can further reduce NTD rates. We have a unique opportunity to evaluate folate supplement effect on mutation rate by leveraging previously collected biological samples from NTD patients and controls from several distinct cohorts. Additionally, we propose to use mouse models to better understand the relationship between folate and mutation rates in vivo. The results of this study will provide an explanation of how folate prevents NTDs, and will reveal novel pathways for intervention on folate-resistant NTDs. Hence, the successful completion of the proposed studies is likely to have substantial impact on our understanding of conditions that affect ~6% of births worldwide and constitute one of the major healthcare concerns for the youngest members of society.