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Transcriptome profiles in brains of mice heterozygous for a DYT1 dystonia-associated mutation in the endogenous Tor1a gene

Sara B. Mitchell, Michael S. Chimenti, Hiroyuki Kawano, Tsun Ming Tom Yuen, Ashley E. Sjurson, Sadahiro Iwabuchi, Kevin L Knudtson, Thomas B Bair, Diana Kolbe, View ORCID ProfileN. Charles Harata
doi: https://doi.org/10.1101/825505
Sara B. Mitchell
aDepartment of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
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Michael S. Chimenti
bBioinformatics Division, Iowa Institute of Human Genetics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
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Hiroyuki Kawano
aDepartment of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
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Tsun Ming Tom Yuen
aDepartment of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
cDepartment of Chemical and Biochemical Engineering, University of Iowa College of Engineering, Iowa City, IA 52242, USA
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Ashley E. Sjurson
aDepartment of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
dDepartments of Biomedical Engineering, and Computer Science & Engineering, University of Iowa College of Engineering, Iowa City, IA 52242, USA
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Sadahiro Iwabuchi
aDepartment of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
eDepartment of Integrative Medicine for Longevity, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
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Kevin L Knudtson
fGenomics Division, Iowa Institute of Human Genetics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
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Thomas B Bair
bBioinformatics Division, Iowa Institute of Human Genetics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
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Diana Kolbe
bBioinformatics Division, Iowa Institute of Human Genetics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
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N. Charles Harata
aDepartment of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
gIowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
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  • ORCID record for N. Charles Harata
  • For correspondence: charles-harata@uiowa.edu
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ABSTRACT

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.

  • ABBREVIATIONS

    AAA+
    ATPases associated with various cellular activities
    CBL
    cerebellum
    CTX
    cerebral cortex
    ΔE- torsinA
    mutated form of torsinA
    #DEx
    number of differentially expressed probes or genes
    FC
    fold change
    HEK
    human embryonic kidney cells
    HET
    heterozygous ΔE-torsinA knock-in mouse
    HIP
    hippocampus
    PC
    pheochromocytoma
    PCA
    principal component analysis
    PCn
    n-th principal component
    STR
    striatum
    WT
    wild-type
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    Posted October 31, 2019.
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    Transcriptome profiles in brains of mice heterozygous for a DYT1 dystonia-associated mutation in the endogenous Tor1a gene
    Sara B. Mitchell, Michael S. Chimenti, Hiroyuki Kawano, Tsun Ming Tom Yuen, Ashley E. Sjurson, Sadahiro Iwabuchi, Kevin L Knudtson, Thomas B Bair, Diana Kolbe, N. Charles Harata
    bioRxiv 825505; doi: https://doi.org/10.1101/825505
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    Transcriptome profiles in brains of mice heterozygous for a DYT1 dystonia-associated mutation in the endogenous Tor1a gene
    Sara B. Mitchell, Michael S. Chimenti, Hiroyuki Kawano, Tsun Ming Tom Yuen, Ashley E. Sjurson, Sadahiro Iwabuchi, Kevin L Knudtson, Thomas B Bair, Diana Kolbe, N. Charles Harata
    bioRxiv 825505; doi: https://doi.org/10.1101/825505

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