Characterization of the urofacial syndrome gene

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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.