Jouberin and Nephrocystin in Joubert Syndrome

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DESCRIPTION (provided by applicant): The ciliopathies represent an emerging class of human developmental disorders affecting brain, eye, liver, kidney, digit, skeletal muscle, and lung, all united by disruption of structure or function of the primary cilium. Joubert syndrome (JS) is a ciliopathy, characterized by structural brain anomalies, mental retardation and ataxia, with frequent accompanying retinal blindness, renal failure, polydactyly and hepatic fibrosis. Identifying the pathogenic mechanisms of JS is important for three reasons: 1] A suspicion of a cerebellar disorder frequently leads to pregnancy termination, so understanding these causes can lead to improved predictions about pregnancy outcome. 2] JS has among the highest incidence of co-existent autism among pediatric brain disorders, suggesting what we learn can impact our understanding of more complex disorders. 3] With an improved understanding of basic mechanisms, the field will be in a better position to consider potential treatments. We have identified the genes AHI1, NPHP1, CEP290, ARL13B, and INPP5E as well as several unpublished genes as mutated in patients with JS. We have identified essential signaling functions of these genes in kidney homeostasis, rhodopsin transport, Wnt-, small GTPase-, and phosphatidyl inositol signaling using a combination of mouse modeling, cell biology and biochemical approaches. However, the physiological role of these genes in the pathogenesis of the ciliopathies and the genetic networks remain unknown. The overall goal of this renewal application is to elucidate the developmental, signaling and cell biological mechanisms of the ciliopathy genes underlying the multi- organ involvement in JS, particularly in the context of brain development. We will utilize both traditional and conditional knockout technologies in mouse, genetic modeling in zebrafish, and advanced live-cell imaging capability that will synergize to help advance our understanding of the mechanisms of this important class of disease. PUBLIC HEALTH RELEVANCE: Joubert syndrome is a devastating recessive childhood developmental disorder affecting brain, eye, liver and kidney development, resulting in frequent mental retardation, ataxia, blindness, and renal failure. The underlying causes appear to relate to defects of primary cilia, which are tiny hair-like antennae that extend from most cells. We will study the signaling mechanisms of the genes that others and we have implicated in this disorder in order to understand the basis of these human diseases.