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 其发生率约为千分之一，是第二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，但对这些原因知之甚少。 人类的毁灭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个不同的基因座倾向于 小鼠中的NTD已被鉴定，并代表了人类中生物学上合理的候选基因，然而， 没有一个被确定为影响人类NTD风险的主要基因。此外，最近的研究表明， 确定小鼠和人类之间的神经管闭合部位不同，这表明小鼠模型可能 对于鉴定涉及人类神经管闭合的基因来说并不理想。基因的鉴定 直接了解哪些基因是神经管缺陷， 在神经管闭合过程中表达。然而，科学家们对基因 在Carnegie（C）阶段7-14的假定关键期期间，当人类 神经管形成和闭合。因此，在这项研究中，我们建议分析基因表达的前 在神经管闭合之前或期间（C9-11）的关键阶段，以及神经管闭合之后（C12 -14）的神经孔 使用基因表达系列分析（SAGE）和微阵列的互补技术。这 这种方法将使我们能够定量和推进我们对这些关键过程中基因表达的理解。 期间，并可能确定关键途径和基因，可能涉及NTD。组合 与我们的基因组筛选结果，NTD的小鼠模型，以及具有生物相容性的基因， 参与失败的NTD关闭，候选人将被优先考虑在我们的患者系列评估， 有NTD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.