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) constitutes 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. The goal of this competing renewal is to characterize new JBTS chromosomal loci, identify the causative genes, and functionally validate mutations within the pathogenetic framework. In our published data, we have already: 1] Identified eight major clinical subtypes of JSRD, each with unique diagnostic criteria involving retinal, renal, hepatic, digit, and cerebral cortical manifestations, 2] Mapped the JBTS2 locus, 3] Identified the JBTS3 gene (AHI1), 4] Identified the JBTS4 gene (NPHP1), 5] Mapped and cloned the JBTS5 gene (CEP290), 6] Identified AHI1 mutations in approximately 20% of patients with the pure JS phenotype. 7] Identified CEP290 mutation in approximately 50% of JSRD patients with the oculo-renal form of disease. 8] Identified mutations in the JBTS6 gene in patients with liver involvement, 9] Identified and functionally validated the JBTS8 gene (ARL13B). In our unpublished work, we have 1] Mapped an additional seven (7) novel chromosomal loci, 2] Identified the CEP41 gene as mutated at one of these loci, 3] Ascertained an additional 27 genetically informative families for ongoing evaluation. Because the majority of patients still have unknown cause of disease, this renewal aims to advance knowledge through molecular characterization of new loci and genes, using newly evolving high-throughput techniques, integrated bioinformatics, and 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 promote essential functions of neuronal cilia. Using a variety of positional cloning strategies, coupled with extensive clinical and pedigree information that we have assembled on over 120 genetically informative consanguineous families and over 200 sporadic patients, we are uniquely positioned to identify the genetic underpinnings of JSRD, correlate genotype with phenotype, and build models for the roles of these essential proteins in disease. Of particular interest will be whether there is a correlation between specific genes and the amazing breadth of JSRD phenotypes. Molecular characterization of the JSRDs will lead to a new genetic classification and a better understanding of these disorders. Characterization of the pathogenic mechanisms underlying the JSRDs will lead to improved diagnosis, and will shed light on the genetics of human cerebellar development as well as more complex neurocognitive disorders.
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