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智力低下形式，影响大约3500名男性中的1人，到目前为止还没有治愈的方法。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。这种疾病是由果蝇的Fmr1基因突变引起的，该基因在果蝇中只有一个同源基因：dFmr1。为了揭开在脆性X综合征疾病机制中扮演关键角色的新角色，我们最近开发并进行了一项关于果蝇中dFmr1过度表达的主导修饰因子的遗传筛选。我们确定了一个主要的常染色体修饰基因，并将其定位到致死的(2)巨型幼虫(I(2)g1)基因座。I(2)gl是细胞骨架的一部分，功能缺失突变会导致肿瘤。一方面，LGL Bindsmyosin II与肌球蛋白II和V在基因上相互作用，另一方面，FMR蛋白参与靶mRNAs的运输和翻译调节。此外，后者还与肌球蛋白V结合形成共同的核核素颗粒(RNP)。综上所述，这些数据表明LGL和FMR在物理上结合在一个蛋白质复合体中，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旅行。这一模型的具体预测将在拟议的项目中得到验证：i)i(2)gl表型应与dFmrl突变体的表型重叠；ii)1(2)gl与dFmr1在遗传上相互作用；iii)lgl和Fmr1在共同的蛋白质复合体中关联，无论是直接的，还是通过中间伙伴。

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.