Impairment of translation in neurons as a putative causative factor for autism.
Impairment of translation in neurons as a putative causative factor for autism.
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神经元翻译受损是自闭症的假定致病因素。
DOI：
10.1186/1745-6150-9-16
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发表时间：
2014-07-10
期刊：
影响因子：
5.5
通讯作者：
Rogozin IB
中科院分区：
文献类型：
--
作者：
Poliakov E;Koonin EV;Rogozin IB
在过去的二十年里，在美国，欧洲和亚洲，自闭症和自闭症谱系障碍（ASD）的患病率急剧增加。鉴于翻译在ASD病因学中可能作用的积累数据，我们分析了与ASD相关的罕见同义替换对mRNA稳定性、剪接增强子和沉默子以及密码子使用的潜在影响。我们推测，翻译的微妙损害，导致神经元特异性蛋白质的剂量不平衡，有助于ASD的病因与环境神经毒素协同作用。检测到与ASD相关的罕见同义取代引起的从最佳密码子到次优密码子的统计学显著转变，而对转录本的其他分析特征没有影响。这一结果表明，稀有密码子对参与神经元发育的基因翻译的影响，即使是轻微的程度，也可能有助于在存在侵略性化学背景的情况下ASD的发病机制。这一假设可以通过进一步分析ASD相关突变、直接生物化学表征其作用以及评估动物模型的体内作用来检验。似乎环境危害与遗传变异的协同作用本身具有有限的或没有有害影响，但被环境因素加强，这是ASD患病率惊人增加的一般原则。本文由Andrey Rzhetsky，Neil R. Smalheiser和Shamil R.苏尼亚耶夫
A dramatic increase in the prevalence of autism and Autistic Spectrum Disorders (ASD) has been observed over the last two decades in USA, Europe and Asia. Given the accumulating data on the possible role of translation in the etiology of ASD, we analyzed potential effects of rare synonymous substitutions associated with ASD on mRNA stability, splicing enhancers and silencers, and codon usage. We hypothesize that subtle impairment of translation, resulting in dosage imbalance of neuron-specific proteins, contributes to the etiology of ASD synergistically with environmental neurotoxins. A statistically significant shift from optimal to suboptimal codons caused by rare synonymous substitutions associated with ASD was detected whereas no effect on other analyzed characteristics of transcripts was identified. This result suggests that the impact of rare codons on the translation of genes involved in neuron development, even if slight in magnitude, could contribute to the pathogenesis of ASD in the presence of an aggressive chemical background. This hypothesis could be tested by further analysis of ASD-associated mutations, direct biochemical characterization of their effects, and assessment of in vivo effects on animal models. It seems likely that the synergistic action of environmental hazards with genetic variations that in themselves have limited or no deleterious effects but are potentiated by the environmental factors is a general principle that underlies the alarming increase in the ASD prevalence. This article was reviewed by Andrey Rzhetsky, Neil R. Smalheiser, and Shamil R. Sunyaev.
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