Characterization of a novel Fragile X interacting gene

描述（申请人提供）：脆性X综合征是最常见的遗传性精神发育迟滞形式，影响约1/3500的男性，迄今尚未治愈。患者具有多效性表型，包括精神发育迟滞、面部畸形以及注意力缺陷和多动障碍。这种疾病是由Fmr 1基因突变引起的，该基因在果蝇中有一个同源物：dFmr 1。为了揭示在脆性X综合征的疾病机制中具有关键作用的新参与者，我们最近开发并进行了果蝇中dFmr 1过表达的主要修饰剂的遗传筛选。我们确定了一个主要的常染色体修饰因子，我们将其定位到致死性（2）巨大幼虫（I（2）gl）基因座。I（2）gl是细胞骨架的一个组成部分，功能缺失突变导致肿瘤。一方面，Lgl结合肌球蛋白II并与肌球蛋白II和肌球蛋白V两者发生遗传相互作用，另一方面，FMR蛋白参与靶mRNA的转运和翻译调节。此外，后者与肌球蛋白V结合形成共同的核糖核颗粒（RNP）。总之，这些数据表明，Lgl和FMR在蛋白质复合物中物理缔合，可能是配备有分子马达的RNP，其能够在由微管和微丝网络组成的主要细胞高速公路上行进。该模型的具体预测将在拟议的项目中进行测试：i）I（2）gl表型应与dFmrl突变体的表型重叠; ii）I（2）gl与dFmrl在遗传上相互作用; iii）Lgl和Fmrl在共同的蛋白质复合物中缔合，无论是直接缔合还是通过中间伴侣缔合。

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.