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

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 (?GAG) 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 is 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. Our goal was to identify key molecular pathways and regulatory networks involved in early neurodevelopment that may be disrupted in the presence of the ?GAG mutation. Through differential gene expression analysis, we sought to uncover potential alterations related to extracellular signalling, lipid homeostasis, and nuclear regulatory mechanisms. This study aims to advance our understanding of the early developmental mechanisms underpinning DYT-TOR1A dystonia and provide a foundation for further investigation into disease-specific molecular targets. Overall design: RNA-seq profiling of induced pluripotent stem cells of symptomatic patients of DYT-TOR1A dystonia and healthy controls.