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.

同化综合征（VCFS）是常见的常染色体显性遗传疾病。在VCF患者中观察到的几种最常见的异常，至少部分通过扰动基因或基因的神经rest细胞迁移或分化所需的基因来解释。但是，在22q11删除的患者中观察到的其他异常与神经rest细胞迁移或分化并不那么明显。例如，大量有22q11.2缺失的患者具有泌尿生殖异常，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不使可以解释这些患者中广泛而高度可变的表型，但这种复杂疾病也可能是由于几种基因的表达降低所致。在先前的资金周期中的工作导致关键区域的完整物理图和多个基因的识别。尽管已经从该地区分离出许多基因，但迄今为止进行的研究尚未提供有力的证据，表明任何一个基因直接负责DGS/VCF中看到的所有特征。在这个项目中，我们建议通过表达和功能分析来表征所选基因，以确定它们在该疾病病因中的作用。这将有助于确定蛋白质水平降低在综合征发病机理中的影响。我们假设22q11删除区域中可能有序列对转录具有全球影响。因此，提出了实验来确定重排是否正在破坏影响DGS/VCFS相关基因表达的调节元件。最后，我们建议筛选一群没有22q11和其他染色体区域的候选基因突变的患者的队列。这些研究应为我们对DGS/VCF的分子理解做出重大贡献。