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

DGS/VCFS 缺失区域基因的表达和功能研究

• 批准号: 6564042
• 负责人: MARCIA L BUDARF
• 金额: $ 21.13万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564042
• 关键词: autosomal dominant trait; clinical research; congenital oral /facial /cranial defect; disease /disorder etiology; gene deletion mutation; gene expression; genetic mapping; genetic transcription; human subject; molecular genetics; pathologic process; syndrome

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.

腭心面综合征 (VCFS) 是一种常见的常染色体显性遗传疾病。在 VCFS 患者中观察到的几种最常见的异常现象可以至少部分地通过神经嵴细胞迁移或分化所需的一个或多个基因的扰动来解释。然而，在 22q11 缺失患者中观察到的其他异常与神经嵴细胞迁移或分化的相关性并不明显。例如，大量 22q11.2 缺失的患者患有泌尿生殖系统异常，并且大多数患者表现出轻度至重度发育迟缓。虽然单个基因的单倍体不足可以解释这些患者中所见的广泛且高度可变的表型，但这种复杂的疾病也可能是由于多个基因表达减少所致。上一个资助周期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。虽然已从该区域分离出许多基因，但迄今为止进行的研究尚未提供强有力的证据证明任何一种基因直接负责 DGS/VCFS 中所见的所有特征。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对该综合征发病机制的影响。我们假设 22q11 缺失区域中可能存在对转录具有全局影响的序列。因此，建议进行实验来确定重排是否破坏了影响 DGS/VCFS 相关基因表达的调控元件。最后，我们建议对一组没有 22q11 缺失的患者进行 22q11 和其他染色体区域候选基因突变的筛查。这些研究应该对我们对 DGS/VCFS 的分子理解做出重大贡献。