Genes that deregulate mTOR signaling as candidates for autism spectrum disorders

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。尽管有强有力的证据表明与遗传有关，但尚未确定具体的基因。ASD与结节性硬化症（TSC）的共发已被认识多年。TSC是一种由肿瘤抑制基因TSC1和TSC2突变引起的神经发育障碍，它们分别编码错构体和结节蛋白。Tuberin和错构体共同抑制mTOR信号，mTOR信号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因子，mTOR信号在神经可塑性和突触功能中起着至关重要的作用。自然发生的突变，通过磷酸化导致tuberin-错构体复合物失活或下调，导致mTOR信号的异常激活。单倍体不足或TSC蛋白的减少已被证明足以引起突触功能的扰动。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、注意力和学习缺陷有关。NF1缺乏通过磷酸化导致tuberin失活，随后mTOR激活。类似地，脑源性神经营养因子（BDNF）磷酸化tuberin并诱导神经元中mTOR依赖的局部蛋白质合成。Pam （Protein Associated with Myc）是我们鉴定的TSC2蛋白tuberin的一个大蛋白，在许多物种中都是高度保守的，在大脑中表达最高。果蝇和秀丽隐杆线虫的Pam同源物是神经元特异性的，具有突触生长调节剂的功能。PTEN是mTOR信号传导的另一个重要上游调控因子，PTEN的突变导致tuberin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，并增加了ASD的风险。此外，我们假设影响mTOR信号、TSC1、TSC2、NF1、BDNF、Pam和PTEN的一个或多个基因的遗传变异与ASD的风险有关。我们将利用单核苷酸多态性（SNPs）和单倍型分析，对777个患有ASD的AGRE家族的TSC1、TSC2、NF1、BDNF、Pam和PTEN基因进行基于家族的关联研究，以探索这些假设。此外，我们将对500例ASD患者和250例对照患者的PTEN全编码区进行重测序。如果这些基因中的一个或多个被发现与ASD相关，这不仅将为了解ASD的发病机制开辟新的领域，而且还将指出一种有效的治疗策略，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综合征和结节性硬化症（TSC）。TSC基因调节通过哺乳动物雷帕霉素靶蛋白介导的信号，称为mTOR。mTOR信号在决定大脑神经元如何相互沟通中起着至关重要的作用。该项目将测试控制mTOR信号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关系。

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.