The long-term objectives of this proposal are to genetically map with high resolution a recessive mouse mutation that predisposes to the development of polycystic kidney disease. This analysis can presently be expedited using PCR-based strategies, and may serve to identify candidate genes which, when mutated, result in this disease. Genetic mapping has directly facilitated the molecular characterization of a number of human disorders. Examples include cystic fibrosis and neurofibromatosis, for which the identification of flanking markers enabled investigators to identify the mutant gene by positional cloning. Similarly, mapping of the dominant familial cardiac hypertrophy trait to human chromosome 14 served to identify cardiac myosin as a candidate gene for a role in this disease. At present, little is known about the molecular basis of polycystic disease. One locus has been identified on human chromosome 16 which appears responsible for the development of dominantly inherited polycystic disease, and efforts to clone this gene are in progress. Linkage analysis for the localization of the genes which cause recessively-inherited polycystic disease is presently not feasible, due to the early lethality and relative rarity of this disorder. An alternative approach to the identification of genes that predispose to polycystic kidney diseases may potentially be accomplished by the study of mouse mutations. There are at least five mutations which cause polycystic kidneys: cpk (congenital polycystic kidney), pcy (progressive cystic kidney), spk (spongy kidney), 1330 (not named), and jck (juvenile cystic kidney). This last mutation is one that I have discovered and am presently characterizing. Recent developments in genetic analysis and molecular techniques make it technically feasible to map the jck trait with high resolution. This will be done using PCR-based analysis of its linkage with genetic markers in a cross between inbred laboratory strains (C57B1/6J and DBA/2J) and in an interspecific cross between C57B1/6J and M. castaneus mice. This mapping analysis may identify candidate genes that are responsible for the development of polycystic kidney disease. These candidate loci can then be tested for abnormalities using molecular techniques such as SSCP (single-strand conformer polymorphism) analysis to assess if these genes are mutant in the jck mice.
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