Congenital ataxia presents in early childhood with non-progressive hypotonia, gross and fine motor delay and cognitive delays. These disorders are distinct from the progressive ataxias because of the presence of congenital cerebellar malformations and because they are typically inherited recessively. Joubert Syndrome and Related Disorders (JSRD) constitute a major subset of these conditions, consisting of a cerebellar midline (vermis) malformation, a nearly pathognomonic Molar Tooth sign on brain Imaging (MTI) and co-existent oculomotor apraxia and episodic breathing dysrhythmias. In our published data, we have: 1] Identified ten unique genetic causes of JSRD (nearly half of the published causes), 2] Generated genotype-phenotype correlations involving cerebellar, retinal, renal, hepatic, digit, and cerebral manifestations. 3] Identified common founder mutations that allow for population-based screening. 4] Discovered that JSRD encoded proteins localize to the cilium. 5] Identified ciliary defects in cells with JSRD mutations. 6] Performed siRNA cell-based screens for defective ciliogenesis to prioritize candidate JSRD genes. 7] Generated and characterized multiple zebrafish, mouse and human cell culture models for JSRD. 8] Defined the concept of `Ciliary localization' model, in which one JSRD gene is required for ciliary localization of other JSRD proteins. In our unpublished work we have: 1] Recruited an additional 200 JSRD patients without molecular diagnosis. 2] Performed whole exome sequencing (WES) and genetic mapping on an additional 100 JSRD families. 3] Identified an additional 12 novel likely JSRD candidate genes. 4] Begun functional validation of the putative mutations. 5] Developed methods to ultrastructurally interrogate ciliary structure in a high-throughput fashion. The goal of this competing renewal is to identify the remaining `discoverable' genes that when mutated lead to JSRD, functionally validate mutations within the pathogenetic framework, and test the hypothesis that mutations in any proven JSRD gene lead to collapse of the ciliary transition zone by correlating genetic mutations with ultrastructural ciliary defects. Because the majority of patients still have unknown cause of disease, this renewal aims to advance knowledge through molecular characterization of new genes, using newly evolving high-throughput techniques, integrated bioinformatics, and a unique resource of consanguineous families recruited world-wide. We further aim to validate these mutations within a mechanistic framework, and a model that JSRD genes are required for essential ciliary structural components during cerebellar development.
Joubert syndrome is a genetically and phenotypically heterogeneous neurodevelopmental disorder unified by defects of the cellular primary cilium. This work will identify new genetic causes and dissect ciliary defects associated with genetic mutations
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