Abstract
Primary dystonia is a disease characterized by involuntary twisting movements caused by CNS dysfunction without underlying histopathology. DYT1 dystonia is a form of primary dystonia caused by an in-frame GAG deletion (DeltaE302/3) in the TOR1A gene that encodes the endoplasmic reticulum luminal protein torsinA. We show that torsinA is also present in the nuclear envelope (NE), where it appears to interact with substrate, and that the DeltaE302/3 mutation causes a striking redistribution of torsinA from the endoplasmic reticulum to the NE. In addition, DeltaE302/3-torsinA recruits WT torsinA to the NE, potentially providing insight into an understanding of the dominant inheritance of the disease. DYT1 dystonia appears to be a previously uncharacterized NE disease and the first, to our knowledge, to selectively affect CNS function.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism*
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Cell Line
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Cricetinae
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Dystonia Musculorum Deformans / genetics*
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Dystonia Musculorum Deformans / metabolism*
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Dystonia Musculorum Deformans / pathology
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Endoplasmic Reticulum / metabolism
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Genes, Dominant
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Green Fluorescent Proteins
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Humans
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Luminescent Proteins / genetics
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Luminescent Proteins / metabolism
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Mice
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Mice, Transgenic
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Microscopy, Immunoelectron
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Molecular Chaperones*
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Mutation*
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Nuclear Envelope / metabolism*
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Nuclear Envelope / ultrastructure
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Sequence Deletion
Substances
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Carrier Proteins
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Dyt1 protein, mouse
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Luminescent Proteins
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Molecular Chaperones
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Recombinant Fusion Proteins
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TOR1A protein, human
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Green Fluorescent Proteins