Characterization of the urofacial syndrome gene

描述（由申请人提供）：泌尿面部（Ochoa）综合征（UFS, omim# 236730）是一种常染色体隐性遗传病，其特征为先天性阻塞性尿路病变和面部表情异常。患者有遗尿，尿路感染，肾积水和排尿功能障碍，由于神经源性膀胱。先前的全基因组扫描将疾病基因定位在染色体10q23-q24上。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。本研究的目的是利用先进的高通量突变筛选技术，对缺陷基因进行定位克隆。在过去的几十年里，定位克隆已经被用来鉴定许多人类疾病基因，当它们的基因组位置被缩小到小区域，例如几百kb的DNA。由于大多数孟德尔性状是罕见的和散发的，因此很难获得信息丰富的家系来将疾病间隔缩小到如此小的区域。这一现实严重阻碍了疾病表型缺陷基因的表征。目前的UFS间隔包含1.8Mb的基因组DNA，这对于传统的位置克隆来说太大了。因此，我们提出了一种新的克隆策略。我们将使用高通量spectrum medix系统进行突变筛选，并基于人类基因组资源对UFS区间内的所有候选基因进行表征。这种高通量突变筛选系统与人类基因组资源的结合将使我们能够从这1.8Mb的基因组间隔中鉴定出UFS基因。UFS为神经源性膀胱、隐匿性神经源性膀胱和其他排尿功能障碍的研究提供了一个很好的模型。这种毁灭性的疾病影响了大量的美国人和世界上其他国家的人，并且可能受到同样的神经系统先天性疾病的影响。表征UFS将使我们能够建立动物模型来研究神经源性膀胱的分子机制。该方法对人类疾病基因的定位克隆具有重要意义。一旦我们在UFS中证实了这种方法的可行性，就可以应用于克隆基因组间隔较大的人类疾病基因座，例如基因组DNA数Mb甚至10Mb的疾病基因座。

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.