The Hereditary Basis of Neural Tube Defects

出生缺陷是一岁以下儿童死亡的主要原因。神经管缺陷(NTD) 出生缺陷的发生率约为千分之一，是第二种最常见的出生缺陷类型。虽然 有强有力的证据表明NTD的遗传成分，但人们对这些原因知之甚少 人类的破坏性疾病。合理的候选基因来自位置数据(例如，基因组筛选 或细胞遗传学重排)或生物学可行性。例如，至少有60个不同的基因座易患 老鼠中的NTD已经被发现，并代表了人类生物学上可信的候选基因，但 没有一个基因被确定为影响人类NTD风险的主要基因。此外，最近的研究表明 确定神经管关闭位置在小鼠和人类之间不同，这表明小鼠模型可能 对于识别与人类神经管闭合有关的基因来说并不理想。基因的鉴定 关于人类NTDS的直接信息将大大增强人类NTDS的易感性 在神经管关闭过程中表达。然而，科学家们对基因一无所知 在卡内基(C)7-14期的关键时期在人类中的表达 神经管形成并关闭。因此，在这项研究中，我们建议分析前部的基因表达。 神经管关闭之前或期间(C9-11)和紧接(C12-14)后的关键阶段的神经孔 使用基因表达序列分析(SAGE)和微阵列的互补技术。这 方法将使我们能够量化和提高我们对这些关键时期的基因表达的理解 并潜在地确定可能与NTD有关的关键途径和基因。结合在一起 根据我们的基因组筛查结果，NTDS的小鼠模型和具有生物学可行性的基因 参与失败的NTD关闭，候选人将被优先考虑在我们的系列患者和 患有NTDS的家庭。

Birth defects are the leading cause of death in children under one year of age. Neural tube defects (NTD) have a frequency of approximately 1/1000 and are the second most common type of birth defect. Although there is strong evidence for a genetic component to NTD, little is known about the causes of these devastating disorders in humans. Plausible candidate genes come from positional data (e.g., genomic screen or cytogenetic rearrangement) or biological feasibility. For instance, at least 60 different loci predisposing to NTDs in mouse have been identified and represent biologically plausible candidate genes in humans, yet none have been established as major genes influencing human NTD risk. Furthermore, recent studies have determined that neural tube closure sites vary between mice and human, suggesting that mouse models might not be ideal for identifying genes involved in human neural tube closure. The identification of genes predisposing to human NTDs would be substantially enhanced by direct information about what genes are expressed during the process of neural tube closure. However, scientists have no knowledge of gene expression in humans during the presumably critical period from Carnegie (C) stages 7-14 when the human neural tube forms and closes. In this study we therefore propose to analyze gene expression in the anterior neuropore during the critical stages prior to or during (C9-11), and just after (C 12-14) neural tube closure using the complementary techniques of Serial Analysis of Gene Expression (SAGE) and microarrays. This approach will allow us to quantitate and advance our understanding of gene expression during these critical periods and potentially identify critical pathways and genes that may be involved in NTD. In combination with results from our genomic screen, mouse models of NTDs, and genes with biological plausibility for involvement in failed NTD closure, candidates will be prioritized for assessment in our series of patients and families with NTDs.