Javed Sehrish, Selliah Tharushan, Lee Yu-Ju, Huang Wei-Hsiang
Centre for Research in Neuroscience, Department of Neurology and Neurosurgery, The Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.
Centre for Research in Neuroscience, Department of Neurology and Neurosurgery, The Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.
Neurosci Biobehav Rev. 2020 Nov;118:538-567. doi: 10.1016/j.neubiorev.2020.08.009. Epub 2020 Aug 25.
Autism spectrum disorders (ASDs) are a group of heterogenous neurodevelopmental disorders affecting 1 in 59 children. Syndromic ASDs are commonly associated with chromosomal rearrangements or dosage imbalance involving a single gene. Many of these genes are dosage-sensitive and regulate transcription, protein homeostasis, and synaptic function in the brain. Despite vastly different molecular perturbations, syndromic ASDs share core symptoms including social dysfunction and repetitive behavior. However, each ASD subtype has a unique pathogenic mechanism and combination of comorbidities that require individual attention. We have learned a great deal about how these dosage-sensitive genes control brain development and behaviors from genetically-engineered mice. Here we describe the clinical features of eight monogenic neurodevelopmental disorders caused by dosage imbalance of four genes, as well as recent advances in using genetic mouse models to understand their pathogenic mechanisms and develop intervention strategies. We propose that applying newly developed quantitative molecular and neuroscience technologies will advance our understanding of the unique neurobiology of each disorder and enable the development of personalized therapy.
自闭症谱系障碍（ASD）是一组异质性神经发育障碍，每59名儿童中就有1人受其影响。综合征性ASD通常与涉及单个基因的染色体重排或剂量失衡有关。这些基因中的许多对剂量敏感，并调节大脑中的转录、蛋白质稳态和突触功能。尽管分子扰动差异很大，但综合征性ASD具有共同的核心症状，包括社交功能障碍和重复行为。然而，每种ASD亚型都有独特的致病机制和合并症组合，需要个别关注。我们已经从基因工程小鼠身上了解了很多关于这些剂量敏感基因如何控制大脑发育和行为的知识。在这里，我们描述了由四个基因的剂量失衡引起的八种单基因神经发育障碍的临床特征，以及利用基因小鼠模型了解其致病机制和制定干预策略的最新进展。我们建议应用新开发的定量分子和神经科学技术将推进我们对每种疾病独特神经生物学的理解，并促进个性化治疗的发展。
