Genetic and Molecular Etiology of Developmental Kidney and Urinary Tract Abnormalities in the DiGeorge, or 22q11.2, Syndrome.

PROJECT NARRATIVE Congenital anomalies of the kidney and urinary tract (CAKUT) are responsible for up to 50% of worldwide cases of pediatric end-stage kidney failure. CAKUT phenotypes are described in ~30% of patients with DiGeorge/22q11.2 Syndrome, the most common microdeletion syndrome in humans, and are attributable to haploinsufficiency of CRKL. In this proposal we implement a multidisciplinary approach using mouse and human studies to, a) identify the mechanisms by which patients with similar genetic mutations and initiating events manifest very different outcomes and conversely, the mechanisms by which different types of mutations produce similar outcomes, and b) identify novel and potentially actionable pathways that could be amenable to targeted treatments.