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）的根本原因几乎完全未知。尽管有强烈的遗传参与证据，但尚未鉴定出特定的基因。 ASD和结节性硬化症复合物（TSC）的同时存在多年。 ASD的特征存在于25-50％的TSC的个体中，TSC是由肿瘤抑制基因TSC1和TSC2突变引起的神经发育障碍，分别编码Hamartin和tuberin。 Tuberin和Hamartin的功能共同抑制MTOR信号传导，从而调节蛋白质的合成和细胞生长。除了成为细胞生长的关键调节剂外，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。天然发生的突变，导致结核素 - 哈马蛋白复合物通过磷酸化的灭活或下调，导致MTOR信号传导异常激活。单倍不足或TSC蛋白的降低已被证明足以进行突触功能的扰动。 1型神经纤维瘤病（NF1）是与认知，注意力和学习缺陷相关的另一种常见的遗传神经皮肤病。 NF1缺乏会导致结核素通过磷酸化和随后的MTOR激活而失活。同样，脑衍生的神经营养因子（BDNF）磷酸化结核素并诱导神经元中依赖性的局部蛋白质合成。 PAM（与MYC相关的蛋白质）是一种我们鉴定为TSC2蛋白Tuberin的相互作用者的大蛋白，在许多物种中高度保守，并且在大脑中的表达最高。果蝇和秀丽隐杆线虫中的PAM同源物是神经元特异性的，起着突触生长调节剂的作用。 PTEN是MTOR信号传导的另一个重要上游调节剂，PTEN的突变导致结核素磷酸化和MTOR激活。基于这些观察结果，我们假设神经元中MTOR的异常过度激活是学习和与TSC和NF1相关的其他认知缺陷的常见因果途径，并增加了ASD的风险。此外，我们假设一个或多个影响MTOR信号传导，TSC1，TSC2，NF1，BDNF，PAM和PTEN的基因的遗传变化将与ASD的风险有关。我们将通过使用单核苷酸多态性（SNP）进行基于家庭的关联研究来探讨这些假设，并分析了整个TSC1，TSC2，NF1，BDNF，PAM，PAM和PTEN基因的777个家族的整个TSC1，TSC2，NF1，BDNF，PAM和PTEN基因。此外，我们将在500例ASD病例和250个对照中对PTEN的整个编码区域进行重新续订。如果发现其中一个或多个与ASD相关，那么它不仅会破坏理解ASD发病机理的新基础，而且还会表明有效的治疗策略，因为雷帕霉素及其类似物可有效阻止MTOR信号传导。自闭症是一种涉及许多遗传因素的疾病，在其他遗传疾病（例如脆弱的X综合征和结核菌硬化症复合物（TSC））中也可以看到。 TSC基因调节通过雷帕霉素的哺乳动物靶标介导的信号传导，称为MTOR。 MTOR信号传导在确定脑中神经元如何相互交流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，因此与公共卫生有直接相关。