Neuropsychiatric Genetics Research Group, Trinity Translational Medicine Institute- TTMI, St James Hospital, D8, Dublin, Ireland.
Trinity College Institute of Neuroscience, TCIN, Loyd Building, Dublin2, Dublin, Ireland.
Orphanet J Rare Dis. 2018 Jul 11;13(1):113. doi: 10.1186/s13023-018-0857-8.
The mechanisms of neuro-genetic disorders have been mostly investigated in the brain, however, for some pathologies, transcriptomic analysis in multiple tissues represent an opportunity and a challenge to understand the consequences of the genetic mutation. This is the case for Rett Syndrome (RTT): a neurodevelopmental disorder predominantly affecting females that is characterised by a loss of purposeful movements and language accompanied by gait abnormalities and hand stereotypies. Although the genetic aetiology is largely associated to Methyl CpG binding protein 2 (MECP2) mutations, linking the pathophysiology of RTT and its clinical symptoms to direct molecular mechanisms has been difficult.One approach used to study the consequences of MECP2 dysfunction in patients, is to perform transcriptomic analysis in tissues derived from RTT patients or Induced Pluripotent Stem cells. The growing affordability and efficiency of this approach has led to a far greater understanding of the complexities of RTT syndrome but is also raised questions about previously held convictions such as the regulatory role of MECP2, the effects of different molecular mechanisms in different tissues and role of X Chromosome Inactivation in RTT.In this review we consider the results of a number of different transcriptomic analyses in different patients-derived preparations to unveil specific trends in differential gene expression across the studies. Although the analyses present limitations- such as the limited sample size- overlaps exist across these studies, and they report dysregulations in three main categories: dendritic connectivity and synapse maturation, mitochondrial dysfunction, and glial cell activity.These observations have a direct application to the disorder and give insights on the altered mechanisms in RTT, with implications on potential diagnostic criteria and treatments.
神经遗传疾病的发病机制在很大程度上是在大脑中进行研究的，然而，对于某些病理学，多组织的转录组分析为理解遗传突变的后果提供了机会和挑战。雷特综合征（RTT）就是这种情况：一种主要影响女性的神经发育障碍，其特征是目的性运动和语言丧失，伴有步态异常和手部刻板动作。尽管遗传病因学主要与甲基化 CpG 结合蛋白 2（MECP2）突变有关，但将 RTT 的病理生理学与其临床症状与直接分子机制联系起来一直很困难。一种用于研究 MECP2 功能障碍在患者中的后果的方法是对源自 RTT 患者或诱导多能干细胞的组织进行转录组分析。这种方法的成本效益和效率不断提高，极大地加深了对 RTT 综合征复杂性的理解，但也提出了一些关于先前持有的信念的问题，例如 MECP2 的调节作用、不同组织中不同分子机制的影响以及 X 染色体失活在 RTT 中的作用。在这篇综述中，我们考虑了许多不同的转录组分析在不同的患者衍生制剂中的结果，以揭示这些研究中跨研究的差异基因表达的特定趋势。尽管这些分析存在局限性，例如样本量有限，但这些研究之间存在重叠，并报告了三个主要类别中的失调：树突连接和突触成熟、线粒体功能障碍和神经胶质细胞活性。这些观察结果对该疾病具有直接的应用价值，并为 RTT 中的改变机制提供了深入了解，对潜在的诊断标准和治疗方法具有影响。
