GENETIC DETERMINANTS OF NON-SYNDROMIC RENAL HYPODYSPLASIA AND RELATED PHENOTYPES

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) represent an extremely important public health problem, accounting for up to 30-40% of pediatric end-stage renal disease (ESRD) and a significant proportion of adult nephropathy. Among those, non-syndromic renal hypodysplasia (RHD, OMIM %610805) represents one of the most common and severe forms. Despite the common knowledge of a strong genetic component in the determination of the disorder, the genetic bases still remain elusive, requiring efforts to recruit large pedigrees and conduct appropriate genetic studies to map the causative gene(s). Mendelian forms of RHD are undrerecognized and systematic sonographic screening of asymptomatic relatives of affected individuals can allow the ascertainment of extended pedigress and the application of positional cloning approaches. The overall objective of the project is to identify the genetic determinants of non-syndromic renal hypodysplasia and related phenotypes. The specific aims of this project are 5: 1) recruitment of patients with familial and sporadic RHD through extensive clinical and sonographic studies; 2) clinical characterization of genetic isolates and recruitment of patients and large genealogies with RHD; 3) identification and characterization of the genes underlying the chromosomes 1p32-33 and 10q24-25 loci previously identified by our group; 4) chromosomal localization of gene(s) underlying RHD by genome-wide analysis of linkage in pedigrees unlinked to the chromosomes 1p32-33 and 10q24-25 loci; 5) linkage disequilibrium mapping in large genealogies identified in genetic isolates. The discovery of genes associated to RHD could shed new light on kidney development and pathophysiology of diseases leading to renal hypoplasia.