The goal of this project is to determine the molecular mechanisms underlying Joubert syndrome (JS). JS is a recessive, neurodevelopmental disorder defined by the appearance of the ?molar tooth sign? on axial brain MRI. Patients with JS have developmental delays, intellectual disability, and ataxia, while a subset can have extra fingers/toes, abnormal eye movements, and progressive problems with vision, kidney and liver function. More than 35 genes have been identified to cause JS when mutated, and all are required for normal primary cilium function. The primary cilium is an antenna-like projection found on nearly every cell; it extends from the cell body, where it receives and interprets signals, thus allowing cells to respond to their environment. Across the 35 JS-related proteins, many cellular defects are described, but the core disease mechanism(s) has not been identified. The leading candidate is abnormal protein content due to disrupted phosphatidylinositol (PI) sub-type distribution in the ciliary membrane and defective ciliary compartmentalization. To explore these possible disease mechanisms, ciliary PI distribution will be determined across genetic causes by immunofluorescence and live cell imaging. To address the consequences of defective compartmentalization, differences in protein content between controls and cells harboring JS-causal mutations will be identified by mass spectrometry analysis of isolated cilia. Assessing these candidate mechanisms across skin cell lines collected from a large number of people with JS will determine if they are part of the core cellular mechanism(s). In contrast to animal models with completely absent function of JS genes, cells from people with JS more accurately reflect the genetic abnormalities that cause the disorder. Using patient cells to prioritize the most important disease mechanisms is an efficient strategy to identify targets for future precision therapies.
Ciliopathy disorders are unified by their overlapping clinical features and underlying cilia-related biological mechanisms, affecting >1/1000 individuals. This project will identify the key biological mechanisms that cause Joubert syndrome, a common genetic cause of ataxia, developmental delay, and intellectual disability in children. The results will lay the groundwork for developing future treatments for Joubert syndrome, other ciliopathies, and potentially, more common disorders affecting the brain, retina, kidney and liver.
