Genetic Determinants of Non-Syndromic Renal Hypodysplasia

Congenital anomalies of the kidney and urinary tract (CAKUT) represent an important public health problem, accounting for up to 30-40% of pediatric ESRD and a significant proportion of adult nephropathy. The reduced renal mass at birth significantly increases the risk of hypertension and heart failure at later age. Individuals who progress to ESRD are exposed to a dramatic increase in cardiovascular morbidity and mortality. Among different forms of CAKUT, non-syndromic RHD represents one of the most common and severe. Despite the knowledge of a genetic component in its determination, the genetic bases still remain elusive, requiring efforts to recruit large pedigrees and conduct appropriate genetic studies to identify the causative gene(s). We collected a large cohort of patients with familial and sporadic RHD and using linkage approaches, we identified 2 loci underlying this trait on chr. 1p32-33 and 10q2425. We have formulated 3 specific aims for this project. AIM 1: recruitment of patients with familial and sporadic RHD: the goal is to identify and recruit 500 patients with RHD and 30 multiplex families. We will collect medical, genealogical and environmental information and biological samples for genetic studies. AIM 2: meiotic and LD mapping to refine the chromosomes 1p32-33 and 10q24-25 loci: we will reduce the size of these loci by meiotic mapping in unrelated RHD pedigrees to identify the critical recombination breakpoints. To further refine the intervals, we will perform an association/linkage disequilibrium mapping in sporadic patients and affected individual originating from the genetic isolates in Sardinia and Northern Italy. AIM 3: identification and characterization of the genes underlying the chromosomes 1p32-33 and 10q24-25 loci: once the two loci have been maximally reduced we will annotate the genes present in the critical recombinants. We will next sequence the coding regions of the genes in the interval in affected individuals from the families linked to the two loci to discover pathogenic mutations. We will test all promising variants for segregation in families and we will assess allelic frequencies in matched controls. Once the pathogenic mutation is discovered we will perform functional studies to identify the pathogenetic mechanisms. Understanding the genetic bases of these conditions has an extreme potential for understanding, preventing and treating these disorders, reducing the associated cardiovascular morbidity and mort (AHA Program: Scientist Development Grant)