The Hereditary Basis of Neural Tube Defects

描述（由研究者提供）：出生缺陷是一岁以下儿童死亡的主要原因。神经管缺陷（NTD）的频率约为1/1000，是第二常见的出生缺陷类型。虽然有强有力的证据表明NTD有遗传成分，但对人类这些毁灭性疾病的原因知之甚少。可能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，在小鼠中至少有60个不同的易感NTDs的位点已经被确定，并且代表了人类中生物学上合理的候选基因，但没有一个被确定为影响人类NTD风险的主要基因。此外，最近的研究已经确定，神经管闭合位点在小鼠和人类之间存在差异，这表明小鼠模型可能不是确定人类神经管闭合相关基因的理想模型。通过直接了解在神经管闭合过程中哪些基因表达，将大大增强对人类ntd易感性基因的鉴定。然而，科学家们对人类在卡内基(C)阶段7-14这一推测为关键时期的基因表达一无所知，这一时期是人类神经管形成和关闭的时期。因此，在本研究中，我们建议使用基因表达序列分析（SAGE）和微阵列互补技术分析（C9-11）之前或期间以及（c12 -14）神经管闭合后的关键阶段前神经孔中的基因表达。这种方法将使我们能够量化和提高我们对这些关键时期基因表达的理解，并有可能确定可能参与NTD的关键途径和基因。结合我们的基因组筛选结果、NTD小鼠模型以及与NTD关闭失败有关的生物学合理性基因，候选基因将优先用于我们的NTD患者和家庭系列的评估。

DESCRIPTION (provided by investigator): 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.