Genes that deregulate mTOR signaling as candidates for autism spectrum disorders

解除 mTOR 信号传导的基因作为自闭症谱系障碍的候选基因

基本信息

批准号：
7488759
负责人：
VIJAYA RAMESH
金额：
$ 19.69万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-24 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7488759
关键词：
Attention Autistic Disorder Brain Brain-Derived Neurotrophic Factor Caenorhabditis elegans Code Cognitive Cognitive deficits Complex Disease Down-Regulation Drosophila genus Family Fragile X Syndrome Genes Genetic Growth Haplotypes Hereditary Disease Homologous Gene Individual Inherited Lead Learning Mediating Mutation Neurocutaneous Syndromes Neurodevelopmental Disorder Neurofibromatosis 1 Neuronal Plasticity Neurons PTEN gene Pathogenesis Pathway interactions Phosphorylation Plant Roots Play Protein Biosynthesis Proteins Public Health Risk Role Signal Transduction Single Nucleotide Polymorphism Sirolimus Synapses TSC1 gene TSC2 gene Testing Therapeutic Tuberous sclerosis protein complex Tumor Suppressor Genes Variant analog autism spectrum disorder base cell growth human FRAP1 protein human TSC1 protein human TSC2 protein synaptic function

项目摘要

DESCRIPTION (provided by applicant): The root causes of Autism Spectrum Disorders (ASD) remain almost entirely unknown. Despite strong evidence for genetic involvement, no specific genes have yet been identified. The co-occurrence of ASD and Tuberous Sclerosis Complex (TSC) has been recognized for many years. Features of ASD are present in 25- 50 percent of individuals with TSC, a neurodevelopmental disorder caused by mutations in tumor suppressor genes TSC1 and TSC2, encoding hamartin and tuberin respectively. Tuberin and hamartin function together to inhibit mTOR signaling, which regulates protein synthesis and cell growth. In addition to being a critical regulator of cell growth, mTOR signaling plays an essential role in neural plasticity and synapse function. Naturally occurring mutations, resulting in inactivation or downregulation of the tuberin-hamartin complex through phosphorylation, lead to aberrant activation of mTOR signaling. Haploinsufficiency or a reduction in TSC proteins has been shown to be sufficient for perturbations of synapse function. Neurofibromatosis type 1 (NF1), is another common inherited neurocutaneous disorder associated with cognitive, attention and learning deficits. NF1 deficiency results in tuberin inactivation through phosphorylation, and subsequent mTOR activation. Similarly, brain-derived neurotrophic factor (BDNF) phosphorylates tuberin and induces mTOR- dependent local protein synthesis in neurons. Pam (Protein Associated with Myc), a large protein that we identified as an interactor of the TSC2 protein tuberin, is highly conserved across many species and has the highest expression in brain. Pam homologs in Drosophila and C. elegans are neuron-specific and function as synaptic growth regulators. PTEN is another important upstream regulator of mTOR signaling, and mutations in PTEN result in tuberin phosphorylation and mTOR activation. Based on these observations, we hypothesize that aberrant hyperactivation of mTOR in neurons is a common causal pathway for learning and other cognitive deficits associated with TSC and NF1, and increases risk for ASD. Further, we hypothesize that inherited variations in one or more genes that influence mTOR signaling, TSC1, TSC2, NF1, BDNF, Pam and PTEN will be associated with risk for ASD. We will explore these hypotheses by conducting family-based association studies using single-nucleotide polymorphisms (SNPs) and haplotype analyses spanning the entire TSC1, TSC2, NF1, BDNF, Pam, and PTEN genes in 777 AGRE families with ASD. In addition, we will carry out re-sequencing of the entire coding region of PTEN in 500 ASD cases and 250 controls. If one or more of these genes is found to be associated with ASD, it would not only break new ground for understanding the pathogenesis of ASD, but would also indicate an effective therapeutic strategy, since rapamycin and its analogs are effective in blocking mTOR signaling. Autism, a disorder that involves many genetic factors, is also seen in other genetic diseases such as Fragile X syndrome and Tuberous Sclerosis Complex (TSC). TSC genes regulate signaling mediated through mammalian target of rapamycin, referred to as mTOR. mTOR signaling plays an essential role in determining how neurons in brain communicate with each other. This project will test whether genes that control mTOR signaling are associated with an increased risk for Autism Spectrum Disorders, and thus has direct relevance to public health.

描述（由申请人提供）：自闭症谱系障碍（ASD）的根本原因仍然几乎完全未知。尽管有强有力的证据表明与遗传有关，但尚未确定具体的基因。自闭症谱系障碍 (ASD) 和结节性硬化症 (TSC) 的共存现象已被认识多年。 25-50% 的 TSC 患者存在 ASD 特征，TSC 是一种由分别编码错构蛋白和马铃薯蛋白的肿瘤抑制基因 TSC1 和 TSC2 突变引起的神经发育障碍。马铃薯蛋白和错构瘤蛋白共同发挥作用，抑制 mTOR 信号传导，从而调节蛋白质合成和细胞生长。 mTOR 信号除了作为细胞生长的关键调节因子外，还在神经可塑性和突触功能中发挥着重要作用。自然发生的突变会通过磷酸化导致马铃薯蛋白-错构蛋白复合物失活或下调，从而导致 mTOR 信号传导异常激活。单倍体不足或 TSC 蛋白减少已被证明足以扰动突触功能。 1 型神经纤维瘤病 (NF1) 是另一种常见的遗传性神经皮肤疾病，与认知、注意力和学习缺陷相关。 NF1 缺陷导致马铃薯蛋白通过磷酸化失活，并随后激活 mTOR。同样，脑源性神经营养因子 (BDNF) 磷酸化马铃薯蛋白并诱导神经元中 mTOR 依赖性局部蛋白质合成。 Pam（与 Myc 相关的蛋白）是一种大蛋白，我们将其确定为 TSC2 蛋白马铃薯蛋白的相互作用蛋白，在许多物种中高度保守，并且在大脑中表达最高。果蝇和线虫中的 Pam 同系物具有神经元特异性，可作为突触生长调节剂。 PTEN 是 mTOR 信号传导的另一个重要上游调节因子，PTEN 的突变会导致马铃薯球蛋白磷酸化和 mTOR 激活。基于这些观察，我们假设神经元中 mTOR 的异常过度激活是与 TSC 和 NF1 相关的学习和其他认知缺陷的常见因果途径，并增加 ASD 的风险。此外，我们假设影响 mTOR 信号传导的一个或多个基因（TSC1、TSC2、NF1、BDNF、Pam 和 PTEN）的遗传变异将与 ASD 风险相关。我们将通过使用单核苷酸多态性 (SNP) 和单倍型分析进行基于家族的关联研究来探索这些假设，涵盖 777 个患有 ASD 的 AGRE 家族的整个 TSC1、TSC2、NF1、BDNF、Pam 和 PTEN 基因。此外，我们还将对 500 名 ASD 病例和 250 名对照者的 PTEN 整个编码区进行重新测序。如果发现这些基因中的一个或多个与 ASD 相关，那么它不仅将为理解 ASD 的发病机制开辟新天地，而且还表明一种有效的治疗策略，因为雷帕霉素及其类似物可以有效阻断 mTOR 信号传导。自闭症是一种涉及多种遗传因素的疾病，也见于其他遗传性疾病，如脆性 X 综合征和结节性硬化症 (TSC)。 TSC 基因调节通过哺乳动物雷帕霉素靶点（称为 mTOR）介导的信号传导。 mTOR 信号传导在确定大脑神经元如何相互通信方面发挥着重要作用。该项目将测试控制 mTOR 信号传导的基因是否与自闭症谱系障碍风险增加相关，从而与公共健康直接相关。