Faculty of Medicine, Department of Medical Genetics, Hacettepe University, Ankara, Türkiye.
Institute of Health Sciences, Department of Medical and Surgical Research, Hacettepe University, Ankara, Türkiye.
Mol Biol Rep. 2024 Sep 13;51(1):979. doi: 10.1007/s11033-024-09915-6.
Rett syndrome (RTT) is a rare neurodevelopmental disorder that primarily affects females and is characterized by a period of normal development followed by severe cognitive, motor, and communication impairment. The syndrome is predominantly caused by mutations in the MECP2. This study aimed to use comprehensive multi-omic analysis to identify the molecular and metabolic alterations associated with Rett syndrome.
Transcriptomic and metabolomic profiling was performed using neuron-like cells derived from the fibroblasts of 3 Rett syndrome patients with different MECP2 mutations (R168X, P152R, and R133C) and 1 healthy control. Differential gene expression, alternative splicing events, and metabolite changes were analyzed to identify the key pathways and processes affected in patients with Rett syndrome. Transcriptomic analysis showed there was significant down-regulation of genes associated with the extracellular matrix (ECM) and cytoskeletal components, which was particularly notable in patient P3 (R133C mutation), who had non-random X chromosome inactivation. Additionally, significant changes in microtubule-related gene expression and alternative splicing events were observed, especially in patient P2 (P152R mutation). Metabolomic profiling showed that there were alterations in metabolic pathways, particularly up-regulation of ketone body synthesis and degradation pathways, in addition to an increase in free fatty acid levels. Integrated analysis highlighted the interplay between structural gene down-regulation and metabolic shifts, underscoring the adaptive responses to cellular stress in Rett neurons.
The present findings provide valuable insights into the molecular and metabolic landscape of Rett syndrome, emphasizing the importance of combining omic data to enlighten the molecular pathophysiology of this syndrome.
雷特综合征（RTT）是一种罕见的神经发育障碍，主要影响女性，其特征是在经历一段正常发育后，出现严重的认知、运动和沟通障碍。该综合征主要由 MECP2 基因突变引起。本研究旨在使用综合多组学分析来鉴定与雷特综合征相关的分子和代谢改变。
使用源自 3 名具有不同 MECP2 突变（R168X、P152R 和 R133C）的雷特综合征患者和 1 名健康对照的成纤维细胞衍生的神经元样细胞进行转录组和代谢组学分析。分析差异基因表达、选择性剪接事件和代谢物变化，以鉴定雷特综合征患者受影响的关键途径和过程。转录组分析显示，与细胞外基质（ECM）和细胞骨架成分相关的基因显著下调，这在患者 P3（R133C 突变）中尤为明显，其存在非随机 X 染色体失活。此外，还观察到微管相关基因表达和选择性剪接事件的显著变化，特别是在患者 P2（P152R 突变）中。代谢组学分析表明，代谢途径发生改变，特别是酮体合成和降解途径上调，此外游离脂肪酸水平升高。综合分析强调了结构基因下调和代谢变化之间的相互作用，突出了 Rett 神经元对细胞应激的适应性反应。
本研究结果提供了雷特综合征分子和代谢景观的有价值的见解，强调了结合组学数据阐明该综合征分子病理生理学的重要性。
