Characterization of a novel Fragile X interacting gene

描述（由申请人提供）：脆性X染色体综合征是遗传性智力低下的最常见形式，大约每3500名男性中就有1人患有这种疾病，迄今为止还没有治愈方法。患者具有多效性表型，包括智力低下、面部畸形以及注意力缺陷和多动障碍。这种疾病是由Fmr1基因突变引起的，该基因在果蝇中有一个单一的同源物：dFmr1。为了揭示在脆性X综合征疾病机制中发挥关键作用的新参与者，我们最近开发并进行了果蝇中dFmr1过表达的显性修饰因子的遗传筛选。我们发现了一个主要的常染色体修饰子，我们将其定位到致死(2)巨型幼虫（I(2)gl）位点上。I(2)gl是细胞骨架的一个组成部分，功能突变导致肿瘤的发生。一方面，Lgl结合肌凝蛋白II并与肌凝蛋白II和肌凝蛋白V相互作用，另一方面，FMR蛋白参与靶mrna的转运和翻译调控。此外，后者与肌凝蛋白V结合形成共同的核糖核粒子（RNP）。综上所述，这些数据表明，Lgl和FMR在蛋白质复合体中有物理关联，可能是一个配备了分子马达的RNP，使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) 1(2)gl与dFmr1基因相互作用；iii) Lgl和Fmr1在一个共同的蛋白质复合物中结合，无论是直接的，还是通过一个中间伙伴。

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.