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Background <p><i>DYT-TOR1A</i> is an early-onset generalised movement disorder characterised by involuntary muscle contractions, leading to abnormal postures and repetitive movements. The trinucleotide GAG in-frame deletion (ΔGAG) in the <i>TOR1A</i> gene is the most common Mendelian form of dystonia. The <i>TOR1A</i> gene encodes for TorsinA protein, involved in several molecular functions, including chaperone activity, protein quality control, synaptic vesicle recycling, vesicular trafficking, protein folding, homeostasis of the nuclear envelope integrity, and lipid metabolism. There is increasing evidence that <i>DYT-TOR1A</i> dystonia is a neurodevelopmental disorder, beginning in the period where structural and functional abnormalities manifest early in physiological maturation. Recent publications have highlighted the importance of the extracellular matrix and lipid metabolism in dystonia, processes important to cellular neurodevelopment. In this study we aimed to elucidate the gene expression profiles of mutant <i>DYT-TOR1A</i> patient-derived iPSCs to identify key pathways and differentially expressed proteins involved in the early stages of neurodevelopment.</p> Results <p>Of the 39,065 genes analysed, 1,322 were found to be significantly dysregulated (<i>p</i> &lt; 0.05). For the purposes of this study, we focus on the 36 most significantly dysregulated genes (q &lt; 0.05) and discuss their biological relevance. We identified 28 upregulated and 8 downregulated genes in human <i>DYT-TOR1A</i> patient-derived induced pluripotent stem cells (iPSCs). Most of the encoded proteins constitute fundamental components of extracellular matrix and lipid metabolism, suggesting impairments related to the microenvironment for cell growth, and cell differentiation, membrane fluidity, receptor trafficking, as well as neurodevelopment. In addition, we identified changes in the expression of genes coding for nuclear proteins, suggesting dysregulation in transcription factors involved in development, particularly in the forebrain and hippocampus. Interestingly, a high proportion of dysregulated genes are localised on Chromosome 22q11.23.</p> Conclusions <p>Our study in iPSC-derived from <i>DYT-TOR1A</i> patients shows a transcriptomic profile, which validates previous candidate genes highlighted in other animal models of dystonia. We believe that our results will help elucidate early mechanisms in neurodevelopment of <i>DYT-TOR1A</i> dystonia.</p>

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Transcriptomic profiling of DYT-TOR1A patient-derived iPSC reveals dysregulation in extracellular matrix, lipid metabolism, and Chr22q11.23

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  • 发表日期：

    2025年11月26日

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  • Núria Setó-Salvia,
  • Henry Houlden,
  • Thomas T. Warner

摘要

Background

DYT-TOR1A is an early-onset generalised movement disorder characterised by involuntary muscle contractions, leading to abnormal postures and repetitive movements. The trinucleotide GAG in-frame deletion (ΔGAG) in the TOR1A gene is the most common Mendelian form of dystonia. The TOR1A gene encodes for TorsinA protein, involved in several molecular functions, including chaperone activity, protein quality control, synaptic vesicle recycling, vesicular trafficking, protein folding, homeostasis of the nuclear envelope integrity, and lipid metabolism. There is increasing evidence that DYT-TOR1A dystonia is a neurodevelopmental disorder, beginning in the period where structural and functional abnormalities manifest early in physiological maturation. Recent publications have highlighted the importance of the extracellular matrix and lipid metabolism in dystonia, processes important to cellular neurodevelopment. In this study we aimed to elucidate the gene expression profiles of mutant DYT-TOR1A patient-derived iPSCs to identify key pathways and differentially expressed proteins involved in the early stages of neurodevelopment.

Results

Of the 39,065 genes analysed, 1,322 were found to be significantly dysregulated (p < 0.05). For the purposes of this study, we focus on the 36 most significantly dysregulated genes (q < 0.05) and discuss their biological relevance. We identified 28 upregulated and 8 downregulated genes in human DYT-TOR1A patient-derived induced pluripotent stem cells (iPSCs). Most of the encoded proteins constitute fundamental components of extracellular matrix and lipid metabolism, suggesting impairments related to the microenvironment for cell growth, and cell differentiation, membrane fluidity, receptor trafficking, as well as neurodevelopment. In addition, we identified changes in the expression of genes coding for nuclear proteins, suggesting dysregulation in transcription factors involved in development, particularly in the forebrain and hippocampus. Interestingly, a high proportion of dysregulated genes are localised on Chromosome 22q11.23.

Conclusions

Our study in iPSC-derived from DYT-TOR1A patients shows a transcriptomic profile, which validates previous candidate genes highlighted in other animal models of dystonia. We believe that our results will help elucidate early mechanisms in neurodevelopment of DYT-TOR1A dystonia.