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

• 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
• 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

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基因参与其中，但尚未确定具体的基因。ASD和动脉硬化综合征（TSC）的共同发生已被认识多年。ASD的特征存在于25- 50%的TSC患者中，TSC是一种由肿瘤抑制基因TSC 1和TSC 2突变引起的神经发育障碍，分别编码hamartin和tuberin。hmTOR蛋白和错构蛋白共同作用以抑制mTOR信号传导，其调节蛋白质合成和细胞生长。除了作为细胞生长的关键调节剂之外，mTOR信号传导在神经可塑性和突触功能中起着至关重要的作用。天然存在的突变，导致通过磷酸化的结核菌素-错构蛋白复合物的失活或下调，导致mTOR信号传导的异常激活。单倍不足或TSC蛋白的减少已被证明足以干扰突触功能。1型神经纤维瘤病（NF 1）是另一种常见的遗传性神经皮肤疾病，与认知，注意力和学习缺陷有关。NF 1缺乏导致通过磷酸化的块茎蛋白失活，以及随后的mTOR激活。类似地，脑源性神经营养因子（BDNF）使结节蛋白磷酸化并诱导神经元中的mTOR依赖性局部蛋白质合成。Pam（与Myc相关的蛋白质）是一种我们鉴定为TSC 2蛋白质块茎蛋白相互作用物的大蛋白质，在许多物种中高度保守，在大脑中表达最高。果蝇和C.秀丽线虫是神经元特异性的，并作为突触生长调节剂发挥作用。PTEN是mTOR信号传导的另一个重要上游调节因子，并且PTEN中的突变导致块茎蛋白磷酸化和mTOR活化。基于这些观察结果，我们假设神经元中mTOR的异常超活化是与TSC和NF 1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、TSC 1、TSC 2、NF 1、BDNF、Pam和PTEN的一个或多个基因的遗传变异将与ASD的风险相关。我们将探索这些假设进行基于家庭的关联研究，使用单核苷酸多态性（SNP）和单倍型分析，跨越整个TSC 1，TSC 2，NF 1，BDNF，Pam，和PTEN基因在777个AGRE家庭与ASD。此外，我们还将对500例ASD病例和250例对照的PTEN全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，这不仅将为理解ASD的发病机制开辟新的领域，而且还将表明有效的治疗策略，因为雷帕霉素及其类似物可有效阻断mTOR信号传导。自闭症是一种涉及许多遗传因素的疾病，也见于其他遗传疾病，如脆性X综合征和多发性硬化症（TSC）。TSC基因调节通过雷帕霉素的哺乳动物靶标（称为mTOR）介导的信号传导。mTOR信号在决定大脑中的神经元如何相互通信中起着至关重要的作用。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的风险增加有关，从而与公共卫生直接相关。