TY - JOUR T1 - Transcriptome profiles in brains of mice heterozygous for a DYT1 dystonia-associated mutation in the endogenous <em>Tor1a</em> gene JF - bioRxiv DO - 10.1101/825505 SP - 825505 AU - Sara B. Mitchell AU - Michael S. Chimenti AU - Hiroyuki Kawano AU - Tsun Ming Tom Yuen AU - Ashley E. Sjurson AU - Sadahiro Iwabuchi AU - Kevin L Knudtson AU - Thomas B Bair AU - Diana Kolbe AU - N. Charles Harata Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/10/31/825505.abstract N2 - In patients with the brain disorder dystonia, body movement is severely affected – with involuntary muscle contractions and abnormal postures, causing extensive deterioration of the patient’s quality of life. The most common inherited form of this disorder is DYT1 dystonia, which is caused by a mutation in TOR1A gene and autosomal dominant. The molecular mechanisms that underlie the effects of the TOR1A mutation on brain function remain unclear. To understand these, we examined the gene expression profiles (transcriptome) in four brain regions (cerebral cortex, hippocampus, striatum and cerebellum) in a mouse model, the heterozygous ΔE-torsinA knock-in mice which genetically reproduce the mutation in DYT1 dystonia. The samples were obtained at 2 to 3 weeks of age, a period during which synaptic abnormalities have been reported. Pairwise comparisons of brain regions revealed differential gene expression irrespective of genotype. A comparison of heterozygous to wild-type mice failed to reveal genotype-dependent differences in gene expression in any of the four brain regions when examined individually. However, genotype-dependent differences became apparent when the information for all brain regions was combined. These results suggest that any changes in the transcriptome within a brain region were subtle at this developmental stage, but that statistically significant changes occur across all brain regions. Such changes in the transcriptome, although subtle in degree, could underlie the processes that give rise to DYT1 dystonia.AAA+ATPases associated with various cellular activitiesCBLcerebellumCTXcerebral cortexΔE- torsinAmutated form of torsinA#DExnumber of differentially expressed probes or genesFCfold changeHEKhuman embryonic kidney cellsHETheterozygous ΔE-torsinA knock-in mouseHIPhippocampusPCpheochromocytomaPCAprincipal component analysisPCnn-th principal componentSTRstriatumWTwild-type ER -