Expression and functional studies of genes in the DGS/VCFS deleted regions

心血管综合征(VCFS)是一种常见的常染色体显性遗传病。在VCFS患者中观察到的几种最常见的异常可以至少部分地解释为神经脊细胞迁移或分化所需的一个或多个基因的扰动。然而，在22q11缺失患者中观察到的额外异常并不明显地与神经脊细胞迁移或分化有关。例如，相当数量的22q11.2缺失患者有生殖泌尿系统异常，大多数患者表现出轻度到严重的发育迟缓。虽然单个基因的单倍体不足可以解释这些患者中广泛且高度可变的表型，但这种复杂的疾病也可能是由于几个基因表达减少所致。在前一个资金周期中的工作导致了关键区域的完整物理图谱和多个基因的识别。虽然已经从该区域分离出许多基因，但到目前为止进行的研究还没有提供强有力的证据，证明任何一个基因直接负责DGS/VCFS的所有特征。在这个项目中，我们建议通过表达和功能分析来表征选定的基因，以确定它们在这种疾病的病因学中的作用。这将有助于确定蛋白质水平降低在综合征发病机制中的作用。我们推测22q11缺失区域中可能存在对转录具有全局影响的序列。因此，建议进行实验以确定重排是否扰乱了影响DGS/VCFS相关基因表达的调控元件。最后，我们建议筛查一组没有22q11缺失的患者，以寻找22q11和其他染色体区域候选基因的突变。这些研究将为我们从分子水平上理解DGS/VCFS做出重要贡献。

Velocardiofacial syndrome (VCFS) is a common, autosomal dominant genetic disorder. Several of the most frequent abnormalities observed in patients with VCFS can be explained, at least in part, by perturbation of a gene, or genes, required for neural crest cell migration or differentiation. However, additional abnormalities observed in the 22q11 deleted patients are not as clearly associated with neural crest cell migration or differentiation. For example, a significant number of patients with 22q11.2 deletions have genitourinary abnormalities and the majority of patients exhibit mild to severe developmental delay. While haploinsufficiency for a single gene could explain the broad and highly variable phenotypes seen in these patients, it is also possible that this complex disorder is due to reduced expression of several genes. Work in the previous funding cycle led to a complete physical map of the critical region and the identification of multiple genes. While numerous genes have been isolated from this region, studies performed thus far have not provided strong evidence for any one gene being directly responsible for all of the features seen in DGS/VCFS. In this project we propose to characterize selected genes by expression and functional analysis to determine their role in the etiology of this disorder. This will help determine the effect of reduced levels of the proteins in the pathogenesis of the syndrome. We hypothesize that there may be sequences in the 22q11 deleted region that have a global effect on transcription. Thus, experiments are proposed to determine whether the rearrangements are disrupting regulatory elements that influence the expression of DGS/VCFS-related gene. Finally, we propose to screen a cohort of patients who do not have deletions of 22q11 for mutations in candidate genes from 22q11 and other chromosomal regions. These studies should make a significant contribution to our molecular understanding of DGS/VCFS.