Congenital ataxia presents in early childhood with non-progressive hypotonia, gross motor, fine motor 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 frequently localize to the cilium. 5] Identified ciliary transition zone (TZ) 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 In our unpublished data we have: 1] Recruited an additional 200 JSRD patients without molecular diagnosis. 2] Performed whole exome (WES) and whole genome sequencing (WGS) on an additional 100 JSRD families. 3] Identified an additional 12 novel likely JSRD candidate genes. 4] Generated IPSCs and cerebellar organoids from mutation-positive and negative families to aid in functional analysis and gene discovery using RNAseq. 5] Begun functional validation of the putative mutations. 6] Developed methods to interrogate ciliary structure in a high-throughput fashion with electron microscopy (EM). The goal of this competing renewal is to identify the remaining ?discoverable? genes that lead to JSRD when lost, functionally validate mutations within the pathogenetic framework, and test the hypothesis that mutations in JSRD genes lead to collapse of the ciliary TZ. 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 in patient cells, within a mechanistic framework 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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