IDENTIFICATION & ANALYSES OF THE UROFACIAL SYNDROME GENE

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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.