Novel Pathogenic Mechanisms of Joubert Syndrome

ABSTRACT Inherited retinal degeneration is a leading cause of irreversible blindness in children. There is currently no effective therapy for any of these diseases except RPE65. The systemic manifestations of the syndromic forms of ciliary degeneration make them a particularly challenging form of the inherited retinal degeneration family to treat. Joubert syndrome is a rare inherited form of retinal degeneration in which patients die prematurely and which has specific defects localized to the connecting cilium of photoreceptors. ARMC9 is a recently discovered gene that has been implicated in Joubert syndrome. This application seeks to identify the mechanism underlying the interplay between the loss of ARMC9 and impaired mitochondrial function in cilia formation. We have strong preliminary data supporting a novel link between mitochondrial function and ciliogenesis. We hypothesize that augmentation of mitochondrial function in ARMC9 mutations will rescue the loss of function. We aim to (1) dissect the mechanism by which mitochondrial proteins contribute to ARMC9 localization, (2) determine whether NMNAT overexpression rescues the loss of ARMC9, (3) determine whether CRISPR-mediated gene editing of ARMC9 restores photoreceptor formation in human iPSC-organoids. These studies will further our understanding of mitochondrial and ciliary function and facilitate the discovery of new therapies for ciliary disorders, including photoreceptor degeneration.