Division of Development and Differentiation, National Institute of Neuroscience, 4-1-1 Ogawahigashi-machi, Kodaira, Tokyo 187-8502, Japan.
Cell Biol Int. 2009 Dec 16;34(1):13-9. doi: 10.1042/CBI20090250.
The molecular pathogenesis of ASD (autism spectrum disorder), one of the heritable neurodevelopmental disorders, is not well understood, although over 15 autistic-susceptible gene loci have been extensively studied. A major issue is whether the proteins that these candidate genes encode are involved in general function and signal transduction. Several mutations in genes encoding synaptic adhesion molecules such as neuroligin, neurexin, CNTNAP (contactin-associated protein) and CADM1 (cell-adhesion molecule 1) found in ASD suggest that impaired synaptic function is the underlying pathogenesis. However, knockout mouse models of these mutations do not show all of the autism-related symptoms, suggesting that gain-of-function in addition to loss-of-function arising from these mutations may be associated with ASD pathogenesis. Another finding is that family members with a given mutation frequently do not manifest autistic symptoms, which possibly may be because of gender effects, dominance theory and environmental factors, including hormones and stress. Thus epigenetic factors complicate our understanding of the relationship between these mutated genes and ASD pathogenesis. We focus in the present review on findings that ER (endoplasmic reticulum) stress arising from these mutations causes a trafficking disorder of synaptic receptors, such as GABA (gamma-aminobutyric acid) B-receptors, and leads to their impaired synaptic function and signal transduction. In the present review we propose a hypothesis that ASD pathogenesis is linked not only to loss-of-function but also to gain-of-function, with an ER stress response to unfolded proteins under the influence of epigenetic factors.
自闭症谱系障碍（ASD）是一种遗传性神经发育障碍，其分子发病机制尚未完全阐明，尽管已有 15 个以上的自闭症易感基因座被广泛研究。一个主要问题是这些候选基因编码的蛋白质是否参与一般功能和信号转导。在 ASD 中发现的突触粘附分子（如 neuroligin、neurexin、CNTNAP（接触蛋白相关蛋白）和 CADM1（细胞粘附分子 1））的基因突变表明，突触功能障碍是潜在的发病机制。然而，这些突变的基因敲除小鼠模型并未显示出所有与自闭症相关的症状，这表明除了这些突变引起的功能丧失外，功能获得也可能与 ASD 的发病机制有关。另一个发现是，具有特定突变的家族成员通常不会表现出自闭症症状，这可能是因为性别效应、显性理论和环境因素（包括激素和压力）。因此，表观遗传因素使我们对这些突变基因与 ASD 发病机制之间的关系的理解变得复杂。我们在本综述中重点介绍了这些突变引起的内质网（ER）应激导致突触受体（如 GABA（γ-氨基丁酸）B 受体）运输障碍，并导致其突触功能和信号转导受损的发现。在本综述中，我们提出了一个假设，即 ASD 的发病机制不仅与功能丧失有关，而且与功能获得有关，这与受表观遗传因素影响的未折叠蛋白的 ER 应激反应有关。
