Characterization of a novel Fragile X interacting gene

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DESCRIPTION (provided by applicant): Fragile X syndrome is the most frequent form of inherited mental retardation, affects about 1 in 3,500 males and to date has no cure. Patients have a pleiotropic phenotype that includes mental retardation, facial dismorphia as well as attention deficit and hyperactivity disorder. The disease is caused by mutations in the Fmr1 gene which has a single homolog in Drosophila: dFmr1. To unravel novel players with key roles in the disease mechanism of fragile X syndrome, we recently developed and conducted a genetic screen for dominate modifiers of dFmr1 over-expression in Drosophila. We identified a single major autosomal modifier which we mapped to the lethal (2)giant larvae (I(2)gl)locus). I(2)gl is a component of the cytoskeleton and loss of function mutations lead to neoplastic tumors. On one hand, Lgl bindsmyosin II and interacts genetically with both myosin II and V and on the other hand, FMR protein is involved in transport and translational regulation of target mRNAs. In addition, the latter associates with myosin V to form a common Ribo-Nuclear Particle (RNP). Taken together this data suggest that Lgl and FMR associate physically in a protein complex, perhaps an RNP equiped with molecular motors which enable its travels on the major cellular highways comprised of microtubule and microfilament networks. Specific predictions of this model will be tested in the proposed project: i) I(2)gl phenotypes should overlap with those of dFmrl mutants; ii) 1(2)gl interacts genetically with dFmr1; iii) Lgl and Fmr1 associate in a common protein complex, be it directly, or through an intermediate partner.