Transcription factor mutationsunderlying birth defects or pediatric cancers

摘要 转录因子(TF)与其DNA结合部位之间的相互作用是一种 细胞内基因调控网络的组成部分。这些相互作用控制着 发育和细胞周期控制的关键步骤。转录因子的突变可导致广泛的 由基因失调引起的一系列结构性出生缺陷或癌症 表情。 加布里埃拉·米勒儿童首创的儿科数据资源中心 (GMKF)儿科研究计划(儿童优先)提供基因组序列和 用于研究儿童癌症或结构性癌症遗传学的表型数据 先天缺陷。需要对GMKF数据进行分析以识别和注释基因 与这些主要儿科疾病相关的变异。 这个项目的目标是：(1)分析来自患者的基因组序列数据 结构性出生缺陷作为儿童识别的第一个数据资源的一部分 预测会损害转录因子结合其DNA靶标的能力的遗传变异 序列；以及(2)对优先排序的一组TF编码执行生化分析 突变体，以表征其假定受损的DNA结合活性。 我们期望我们的结果将有助于识别致病变异。 结构性出生缺陷或儿童癌症，揭示了这些变异的机制 可能导致这些疾病的基因表达失调，导致精致基因组 诊断，并提供关于突变体TF改变的DNA结合活性的数据 为社区提供资源。

ABSTRACT The interactions between transcription factor (TFs) and their DNA binding sites are an integral part of the gene regulatory networks within cells. These interactions control critical steps in development and cell cycle control. Mutations in TFs can result in a wide range of structural birth defects or cancers through the dysregulation of gene expression. The Pediatric Data Resource Center established by the Gabriella Miller Kids First (GMKF) Pediatric Research Program (Kids First) provides genome sequence and phenotype data for studies investigating the genetics of childhood cancers or structural birth defects. Analysis of the GMKF data are needed to identify and annotate genetic variants associated with these major pediatric diseases. The goals of this project are: (1) to analyze genome sequence data from patients with structural birth defects made available as part of the Kids First Data Resource to identify genetic variants predicted to damage the ability of TFs to bind their DNA target sequences; and (2) to perform biochemical assays on a prioritized set of the TF coding variants to characterize their putatively damaged DNA binding activities. We anticipate our results will help to identify pathogenic variants contributing to structural birth defects or pediatric cancers, reveal mechanisms by which such variants may dysregulate gene expression leading to these disorders, lead to refined genomic diagnostics, and provide data on the mutant TFs’ altered DNA binding activities as a resource to the community.