CHARACTERIZATION OF TSC PROTEIN HAMARTIN AND TUBERIN

描述(申请人提供)：结节性硬化症是多系统的 以生长的广泛发展为特征的疾病，称为 错构瘤存在于许多组织和器官，特别是大脑、眼睛、 皮肤、肾脏、心脏、肺和骨骼。受影响最严重的系统是 中枢神经系统与受影响个体的发生 癫痫(80%-90%)、智力低下(50%-60%)和自闭症(高达 50%)。TSC是一种常染色体显性遗传病，但 由于新的生殖系，大约三分之二的受影响患者是零星的 突变。遗传连锁研究表明，这些基因座具有异质性 疾病，在9号和16号染色体上至少有两个TSC决定基因 分别命名为TSC1和TSC2。TSC1基因编码一种新的 含有一个跨膜结构域和一个大的 胞质尾部具有卷曲的卷曲结构域。TSC2基因编码一种新的 含有与GTPase激活同源区域的蛋白质tuberin 蛋白质Rap1GAP。我们已经对该基因进行了全面的突变分析 TSC1和TSC2基因，并指出TSC1突变显著 在零星的患者中代表性不足。然而，第二次的发生 TSC病变，尤其是脑病变中的体细胞突变尚不清楚。在……里面 为了了解这是由于细胞的多形性，还是 Tuberin/Hamartin的单倍体不足足以促进肿瘤的发生 将对激光捕获显微解剖的病变进行遗传分析。我们有 发现一种与Myc相关的新蛋白，名为Pam，是一种相互作用的蛋白质 块茎蛋白的蛋白质。果蝇和线虫的突变 (rpm-1)Pam的同源物显示突触过度生长。我们假设帕姆是一个 Tuberin-hamartin复合体的基本成分，特别是在中枢神经系统 这些蛋白质可能在皮质神经元功能中起关键作用 接受检查。Pam与块茎蛋白相互作用的结构域揭示了90% 与苍蝇同源基因HIW相似。可能的身体和基因 将研究果蝇TSC2产物Gigas和HIW之间的相互作用。 因此，这些研究旨在确定tuberin-hamartin在 哺乳动物中枢神经系统将通过果蝇模型系统得到进一步加强 基因操作是可能的。在此获得的信息将 阐明这些肿瘤抑制因子的生理功能，这将是 帮助设计更好的疗法。

DESCRIPTION (provided by applicant): Tuberous sclerosis complex is multisystem disorder characterized by the widespread development of growths known as hamartomas in many tissues and organs, particularly within the brain, eyes, skin, kidneys, heart, lungs and skeleton. The most severely affected system is the central nervous system with the occurrence in affected individuals of seizures (80-90 percent), mental retardation (50-60 percent), and autism (up to 50 percent). TSC is inherited as an autosomal dominant disorder, but approximately two-thirds of affected patients are sporadic due to new germline mutations. Genetic linkage studies have shown locus heterogeneity for the disease, with at least two TSC determining genes on chromosomes 9 and 16 which have been termed TSC1 and TSC2 respectively. The TSC1 gene encodes a novel protein, hamartin that contains a single transmembrane domain and a large cytoplasmic tail with a coiled-coil domain. The TSC2 gene encodes a novel protein tuberin that contains a region of homology to the GTPase activating protein rap1GAP. We have performed a comprehensive mutational analysis of the TSC1 and TSC2 genes and noted that TSC1 mutations are significantly underrepresented in sporadic patients. However, the occurrence of the second somatic mutation in TSC lesions, particularly brain lesions is not clear. In order to understand whether this is due to cellular pleomorphism, or if haploinsufficiency of tuberin/hamartin is enough to promote tumor genesis, we will perform genetic analysis on laser capture microdissected lesions. We have identified a novel protein associated with Myc named Pam as an interacting protein for tuberin. Mutations in both the Drosophila (hiw) and C. elegans (rpm-1) homologs of Pam show synaptic overgrowth. Our hypothesis that Pam is an essential component of the tuberin-hamartin complex, particularly in the CNS where these proteins may have a critical role in cortical neuron function will be examined. The domain of Pam that interacts with tuberin reveals 90 percent similarity with the fly homolog HIW. The possible physical and genetic interaction between the Drosophila TSC2 product Gigas and HIW will be examined. Thus the studies aimed at defining the role of tuberin-hamartin in the mammalian CNS will be further strengthened by the Drosophila model system where genetic manipulations are possible. The information obtained here will elucidate the physiological functions of these tumor suppressors, which will aid in designing better therapies.