Characterization of the urofacial syndrome gene

尿面综合征基因的特征

• 批准号: 7080752
• 负责人: CONG-YI WANG
• 金额: $ 19.46万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7080752
• 关键词: autosomal recessive trait; biotechnology; blood tests; congenital disorders; face expression; family genetics; functional /structural genomics; gene expression; gene mutation; genetic disorder; genetic mapping; genetic markers; genetic screening; genotype; high throughput technology; human genetic material tag; human population genetics; human subject; laboratory mouse; neurogenic urinary bladder disorder; pathologic process; positional cloning

DESCRIPTION (provided by applicant): The Urofacial (Ochoa) syndrome (UFS, OMIM #236730) is an autosomal recessive disease characterized by congenital obstructive uropathy and abnormal facial expression. The patients have enuresis, urinary tract infection, hydronephrosis and voiding dysfunction as a result of a neurogenic bladder. Previous genome-wide scan localized the disease gene to chromosome 10q23-q24. Currently, we have analyzed 33 polymorphic SNPs and narrowed the disease gene to a 1.8Mb of genomic DNA between markers D10S2499 and D10S603. The goal of this propossal is to characterize the defective gene by positional cloning with the adavnced high throughput mutation screening techniques. For the past several decades, positional cloning has been used to identify many human disease genes when their genomic locations are narrowed to small regions, e.g., several hundred-kb of DNA. As most of the mendelian traits are rare and sporadic, it is difficult to obtain informative pedigrees to narrow the disease interval to such small regions. This reality significantly hampered the characterization of the defective genes for the disease phenotypes. The current UFS interval contains 1.8Mb of genomic DNA which is too big for conventional positional cloning. As a result, we propose a novel strategy for the cloning. We will use the high throughput SpectruMedix system for mutation screening, and all of the candidate genes within the UFS interval will be characterized based on the human genome resources. This combination of high throughput mutation screening system and human genome resources would allow us to identify the UFS gene from this 1.8Mb of genomic interval. UFS provides an excellent model for the studies of neurogenic bladders, occult neurogenic bladders and other voiding dysfunctions. Such devastating disorders affect a large number of Americans and other people in the world, and are probably affected by the same congenital disorder of neurological origin. Characterization of UFS would allow us to create animal models to study the molecular mechanism underlining neurogenic bladders. The strategy applied in this proposal may have significant implications for positional cloning of the human disease genes. Once we have confirmed the feasibility of this approach in UFS, it can be applied for cloning of human disease loci with large genomic intervals, e.g., those disease loci with several Mb to even 10Mb of genomic DNA.

描述（由申请人提供）：泌尿法（OCHOA）综合征（UFS，OMIM＃236730）是一种常染色体隐性疾病，其特征是先天性阻塞性泌尿病和异常面部表达。由于神经源性膀胱，患者患有遗传性，尿路感染，浮力性和功能障碍。以前的全基因组扫描将疾病基因局部定位于10q23-Q24染色体。目前，我们已经分析了33个多态性SNP，并将疾病基因缩小到标记D10S2499和D10S603之间的1.8MB基因组DNA。该提案的目的是通过使用ad纵发的高吞吐突变筛选技术来表征有缺陷的基因。在过去的几十年中，当位置克隆被用来识别许多人类疾病基因时，当它们的基因组位置缩小到小区域，例如几百kb的DNA。由于大多数孟德尔特征是罕见且零星的特征，因此很难获得信息丰富的血统，以将疾病间隔缩小到如此小的地区。这种现实显着阻碍了疾病表型缺陷基因的表征。当前的UFS间隔包含1.8MB的基因组DNA，对于常规位置克隆来说太大了。结果，我们提出了克隆的新型策略。我们将使用高吞吐量光谱系统进行突变筛选，并且UFS间隔内的所有候选基因将根据人类基因组资源来表征。高通量突变筛选系统和人类基因组资源的这种结合将使我们能够从这个1.8MB的基因组间隔中识别出UFS基因。 UFS为研究神经源性膀胱，神秘神经源性膀胱和其他空隙功能障碍提供了出色的模型。这种毁灭性疾病会影响世界上许多美国人和其他人，并可能患有神经系统起源的先天性疾病。 UF的表征将使我们能够创建动物模型来研究强调神经源性膀胱的分子机制。该提案中应用的策略可能对人类疾病基因的位置克隆具有重要意义。一旦我们确认了这种方法在UFS中的可行性，就可以将其用于以较大的基因组间隔（例如那些具有多个MB至10MB至10MB基因组DNA）的疾病基因瘤来克隆人类疾病基因座。