During the previous funding period we discovered the pathogenic role of two proteins in neurological disease. By positional cloning the mouse neurological mutant pale tremor, with neurodegeneration in peripheral ganglia and CNS, we demonstrated that this disorder is caused by a null mutation of FIG4, a phosphatidyl inositol 5 phosphatase. We identified mutations of human FIG4 in patients with a severe form of Charcot Marie Tooth disease, a peripheral neuropathy. We also found that mutation of the functionally related protein VAC14 mimics the phenotype of the pale tremor mouse. To further evaluate the role of this pathway in neurological disease, we will characterize mouse models of human mutations in FIG4 and dissect the pathogenic contributions of neurons and Schwann cells using conditional mutants. We will evaluate the contribution of VAC14 to Charcot Marie Tooth disease, and extend the analysis of both genes to related neurological disorders. In order to identify additional components of this regulatory pathway, we will clone the modifier locus in strain C57BL/6J that exacerbates clinical progression in FIG4 null mice and investigate the in vivo phenotypes associated with mutation of the third enzyme in this pathway, a phosphoinositide kinase. We will evaluate the interaction of FIG4 with proteins recently identified in a yeast 2 hybrid screen. This work will extend our understanding of the mechanisms of pathogenesis of mutations in FIG4 and VAC14 and better define their contribution to human neurological disease.
During the past funding period, we discovered that a lipid signaling molecule in required for survival of neurons. We found that mutations in a novel mammalian gene change the concentration of this cellular signal and result in severe neurological disease in the mouse. We were also successful in translating this information into the clinical realm by identifying patient mutations and developing molecular diagnosis for Charcot Marie Tooth disorder type 4J. We propose to extend this work to related genes and disorders, and to generate better animal models of the human disease in order to understand the pathogenic mechanism and provide an accurate model for testing therapeutic intervention.
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