GENETIC MAPPING IN THE HYPERCALCIURIC STONE-FORMING RAT

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Idiopathic hypercalciuria (IH) is the most common metabolic abnormality associated with kidney stones in humans, and as many as 45 percent of patients with IH have a family history of nephrolithiasis. Defined subsets of patients with hypercalciuric nephrolithiasis include those with autosomal or X linked inheritance, but overall the phenotype of human IH is that of a complex, polygenic disease. A full-scale investigation of the genetics of human hypercalciuria would be made difficult by the large number of families required, dietary variables, and number of metabolic subsets described in patients with IH. However, an animal model exists in the genetic hypercalciuric stone-forming (GHS) rat, which is now in its 51st generation of inbreeding. The physiology of hypercalciuria in this model has been extensively characterized and resembles human IH in many important respects. The GHS rat colony was established by Dr. David Bushinsky by selectively breeding the most hypercalciuric littermates of each generation, and is likely to be enriched in alleles for genes that contribute to hypercalciuria. A robust armamentarium of tools for genetic and physical mapping in rats is now available, and expanding rapidly. The goal of this project is to map genes determining hypercalciuria in the GHS rat. The first aim of this project is to identify quantitative trait loci (QTL) linked to hypercalciuria through QTL mapping. This analysis will make use of selective genotyping of an F2 intercross between GHS and normocalciuric Wistar-Kyoto (WKY) rats, using simple sequence-length polymorphisms (SSLPs). The second aim is to refine the QTL localization further by constructing and analyzing congenic strains of rats. We have made substantial progress towards a whole-genome scan in an initial F2 of 156 rats, and have identified one QTL on chromosome 1 that meets conservative criteria for significance (LOD 4.5) and two loci that meet criteria "suggestive" of linkage. More precise localization should eventually make possible physical mapping and positional cloning of genes contributing strongly to hypercalciuria, which will allow for future work in which homologues of these genes can be studied to determine their role in human idiopathic hypercalciuria.