IDENTIFICATION & ANALYSES OF THE UROFACIAL SYNDROME GENE

描述：(改编自申请者的摘要)面部(Ochoa) 综合征是一种以常染色体隐性遗传病为特征的疾病 由神经原性膀胱、便秘引起的先天性梗阻性尿路病 和异常的面部表情。系谱分析表明，单个 基因是导致这种综合征的原因。因为多发性肌力衰竭的肌肉功能 器官或组织受累(即膀胱、肠道和面部肌肉)，它 据认为，这种损伤可能存在于大脑的协调区域 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查已经将UFS基因映射到 在10q23-q24上，D10S184和D10S603之间大约1厘米(1Mb)。目标是 这一建议的目的是使用精细作图来识别疾病基因， 位置候选和位置克隆技术。三个具体目标 建议：1.进一步缩小基因组间隔的大小 含有UFS基因的。将使用三种互补的方法来 实现这一目标。前两种方法是基于链接的 不平衡分析和第三种方法试图确定可能的 涉及UFS基因的基因组DNA片段的删除/插入。2. 用位置候选法和/或定位法鉴定UFS基因 位置克隆。将评估UFS间隔中的候选基因 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。如果候选基因分析不能 识别UFS基因，UFS区间中的额外编码序列将 使用包括外显子在内的几种位置克隆技术进行鉴定 诱捕、基因选择和基因组测序。3.刻画 疾病的结构、表达、调节元件和功能 吉恩。拟议的研究应该允许揭示与此有关的基因。 用于UFS。对该基因的鉴定可能会为 大量排尿功能障碍和其他相关的神经泌尿系疾病 这些都是美国和世界的主要健康问题。该基因还可能 对了解其分子基础和正常生理学具有重要意义 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.