IDENTIFICATION & ANALYSES OF THE UROFACIAL SYNDROME GENE

描述：（改编自申请人的摘要）Urofacial（Ochoa） 综合征（UFS，OMIM #236730）是一种常染色体隐性遗传疾病， 由于神经性膀胱引起的先天性梗阻性尿路病，便秘 面部表情异常 系谱分析表明， 基因导致了这种综合症。 因为肌肉的多重功能 涉及器官或组织（即，膀胱，肠和面部肌肉），它 据信病变可能位于协调的大脑区域 肌肉活动，如排尿、排便和面部肌肉运动。 我们最近的基因组筛选已经将UFS基因定位到一个间隔为 在10 q23-q24上的D10 S184和D10 S603之间存在约1cM（1 Mb）的突变。 目标 这个建议的一个重要方面是使用精细定位来识别疾病基因， 定位候选和定位克隆技术。 三个具体目标 建议：1. 为了进一步缩小基因组间隔的大小 含有UFS基因 将采用三种相辅相成的办法， 实现这一目标。 前两种方法是基于联系 不平衡分析和第三种方法旨在确定可能的 涉及UFS基因的基因组DNA片段的缺失/插入。 2. 使用位置候选方法鉴定UFS基因和/或 定位克隆 将评价UFS区间内的候选基因 通过识别突变并评估它们与发生的相关性， 疾病表型和携带者状态的关系。 如果候选基因分析失败， 为了鉴定UFS基因，UFS间隔中的额外编码序列将 使用几种位置克隆技术进行鉴定，包括外显子 捕获、cDNA选择和基因组测序。 3. 表征 疾病的结构、表达、调控元件和功能 基因 拟议中的研究应该允许揭示基因负责 对于UFS。 该基因的鉴定可能会为基因治疗提供重要的见解。 大量排尿功能障碍和其他相关的神经性尿路病 这是美国和世界的主要健康问题。 该基因也可能 对于理解这些疾病的分子基础和正常生理学是很重要的。 神经系统对肌肉活动的协调。

DESCRIPTION: (Adapted from the applicant's abstract) The Urofacial (Ochoa) syndrome (UFS, OMIM #236730) is an autosomal recessive disease characterized by congenital obstructive uropathy due to a neurogenic bladder, constipation and abnormal facial expression. Pedigree analysis has shown that a single gene is responsible for the syndrome. Because muscular function of multiple organs or tissues is involved (i.e., bladder, bowel and facial muscles), it is believed that the lesion may reside in the brain regions that coordinate muscle actions, such as micturition, defecation and facial muscle movement. Our recent genome screen has mapped the UFS gene to an interval of approximately 1cM (1Mb) between D10S184 and D10S603 on 10q23-q24. The goal of this proposal is to identify the disease gene using fine-mapping, positional candidate and positional cloning techniques. Three specific aims are proposed: 1. To further reduce the size of the genomic interval containing the UFS gene. Three complementary approaches will be used to accomplish this aim. The first two approaches are based on linkage disequilibrium analyses and the third approach seeks to identify possible deletions/insertions of genomic DNA fragments involving the UFS gene. 2. To identify the UFS gene using positional candidate approach and/or positional cloning. Candidate genes in the UFS interval will be evaluated by identifying mutations and assessing their correlation with the occurrence of disease phenotype and carrier status. If candidate gene analyses fail to identify the UFS gene, additional coding sequences in the UFS interval will be identified using several positional cloning techniques including exon trapping, cDNA selection and genomic sequencing. 3. To characterize the structure, expression, regulatory elements, and function of the disease gene. The proposed studies should permit revelation of the gene responsible for UFS. Identification of the gene may provide important insight for a large number of voiding dysfunctions and other related neurologic uropathies that are major health problems in the US and the world. The gene may also be important for understanding the molecular basis and normal physiology of the coordination of muscle actions by the nervous system.