Kwan Vickie, Unda Brianna K, Singh Karun K
Department of Biochemistry and Biomedical Sciences, Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario L8S 4K1 Canada.
J Neurodev Disord. 2016 Dec 5;8:45. doi: 10.1186/s11689-016-9176-3. eCollection 2016.
Genetic factors play a major role in the risk for neurodevelopmental disorders such as autism spectrum disorders (ASDs) and intellectual disability (ID). The underlying genetic factors have become better understood in recent years due to advancements in next generation sequencing. These studies have uncovered a vast number of genes that are impacted by different types of mutations (e.g., de novo, missense, truncation, copy number variations).
Given the large volume of genetic data, analyzing each gene on its own is not a feasible approach and will take years to complete, let alone attempt to use the information to develop novel therapeutics. To make sense of independent genomic data, one approach is to determine whether multiple risk genes function in common signaling pathways that identify signaling "hubs" where risk genes converge. This approach has led to multiple pathways being implicated, such as synaptic signaling, chromatin remodeling, alternative splicing, and protein translation, among many others. In this review, we analyze recent and historical evidence indicating that multiple risk genes, including genes denoted as high-confidence and likely causal, are part of the Wingless (Wnt signaling) pathway. In the brain, Wnt signaling is an evolutionarily conserved pathway that plays an instrumental role in developing neural circuits and adult brain function.
We will also review evidence that pharmacological therapies and genetic mouse models further identify abnormal Wnt signaling, particularly at the synapse, as being disrupted in ASDs and contributing to disease pathology.
遗传因素在神经发育障碍如自闭症谱系障碍（ASD）和智力障碍（ID）的风险中起主要作用。由于下一代测序技术的进步，近年来潜在的遗传因素已得到更好的理解。这些研究发现了大量受不同类型突变（例如，新生突变、错义突变、截短突变、拷贝数变异）影响的基因。
鉴于大量的遗传数据，单独分析每个基因并非可行的方法，且需要数年时间才能完成，更不用说尝试利用这些信息开发新的治疗方法了。为了理解独立的基因组数据，一种方法是确定多个风险基因是否在共同的信号通路中发挥作用，这些信号通路可识别风险基因汇聚的信号“枢纽”。这种方法已涉及多个通路，如突触信号传导、染色质重塑、可变剪接和蛋白质翻译等。在本综述中，我们分析了近期和以往的证据，表明多个风险基因，包括被视为高可信度且可能具有因果关系的基因，是无翅型（Wnt信号）通路的一部分。在大脑中，Wnt信号是一条进化上保守的通路，在神经回路发育和成年大脑功能中起重要作用。
我们还将综述证据，表明药物治疗和基因小鼠模型进一步证实ASD中存在异常的Wnt信号，特别是在突触处，且这与疾病病理有关。
