The aims of this project are to apply genetic approaches to elucidate the molecular mechanisms underlying human renal agenesis/hypoplasia. Renal developmental disorders are the most common causes of occurs of cases of end stage renal disease (ESRD) in children. Familial aggregation of renal hypoplasia/agenesis suggests that genetic factors are important in the development of this disorder. We have recruited seven large kindreds ascertained via an index case with agenesis/ hypoplasia; these kindreds demonstrate transmission consistent with autosomal dominant inheritance with reduced penetrance. We have performed a genome-wide scan and analysis of linkage and have detected linkage to chromosome 1p33-32 under a model of dominant inheritance with locus heterogeneity (peak lod score 3.9 with 45% of families linked). Importantly, the first family (K100) supports linkage to the 1p33-32 interval on its own (peak lod score 3.5). Fine mapping of the interval the interval with 26 microsatellite markers confirmed the trait locus to a 7 Mb interval containing 52 genes. This chr 1p33-32 interval is specific for renal hypoplasia as no kindred with primary vesicoureteral reflux demonstrate linkage to this interval. In the current proposal, we will continue characterize and recruit patients with familial and sporadic renal hypoplasia. We will fine map the interval by meiotic and disequilibrium mapping in additional kindreds. We will also annotate and prioritize 52 genes in the interval by gene expression analysis in normal tissue. . We will next proceed with sequencing of the positional candidates to identify underlying gene(s). Once the gene has been identified, we will examine the contribution of this gene to sporadic forms of renal hypoplasia. Identification of the gene(s) for hypoplasia will provide insight in the biology of urogenital development. Moreover, it will provide the opportunity to develop novel diagnostic and therapeutic tools for this common clinical disorder. This project is relevant to public health because renal agenesis/hypoplasia is one of the most common causes of pediatric renal failure, resulting in significant childhood morbidity and mortality. Identification of genes underlying this trait will provide novel approaches to detect patients at risk and may enable the development of novel therapeutic approaches for this disorder ? ? ?
