The aims of this project are to apply genetic approaches to elucidate the molecular mechanisms underlying human renal agenesis/hypodysplasia. Renal developmental disorders are the most common causes 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 15 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 1p32-33 and another locus 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. Fine mapping of the interval with 26 microsatellite markers confirmed the trait locus to a 7 Mb interval containing 52 genes. In a second large dominant pedigree, we have also localized a second gene for this phenotype on chromosome three. We have also recruited additional patients with sporadic forms of disease to study the role of genes in such cohorts. In the current proposal, we will continue to characterize and recruit patients with familial and sporadic renal hypoplasia. We will also annotate and prioritize genes in the chr 1 and chr 3 interval and 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. In addition, we will search for chromosomal structural variations as a underlying cause of sporadic disease. 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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Rasooly, Rebekah S
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Columbia University (N.Y.)
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Sanna-Cherchi, S; Sampogna, R V; Papeta, N et al. (2013) Mutations in DSTYK and dominant urinary tract malformations. N Engl J Med 369:621-9
Thomas, Rosemary; Sanna-Cherchi, Simone; Warady, Bradley A et al. (2011) HNF1B and PAX2 mutations are a common cause of renal hypodysplasia in the CKiD cohort. Pediatr Nephrol 26:897-903