Abstract
An enigmatic feature of many genetic diseases is that mutations in widely expressed genes cause tissue-specific illness. One example is DYT1 dystonia, a neurodevelopmental disease caused by an in-frame deletion (Deltagag) in the gene encoding torsinA. Here we show that neurons from both torsinA null (Tor1a(-/-)) and homozygous disease mutant "knockin" mice (Tor1a(Deltagag/Deltagag)) contain severely abnormal nuclear membranes, although non-neuronal cell types appear normal. These membrane abnormalities develop in postmigratory embryonic neurons and subsequently worsen with further neuronal maturation, a finding evocative of the developmental dependence of DYT1 dystonia. These observations demonstrate that neurons have a unique requirement for nuclear envelope localized torsinA function and suggest that loss of this activity is a key molecular event in the pathogenesis of DYT1 dystonia.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain / abnormalities*
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Brain / metabolism*
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Brain / physiopathology
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Carrier Proteins / metabolism
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Cell Differentiation / genetics
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Cell Movement / genetics
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Cells, Cultured
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Disease Models, Animal
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Dystonia Musculorum Deformans / genetics
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Dystonia Musculorum Deformans / metabolism*
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Dystonia Musculorum Deformans / physiopathology
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Genetic Predisposition to Disease / genetics
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HSC70 Heat-Shock Proteins / metabolism
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Membrane Proteins / metabolism
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Mice
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Mice, Knockout
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Mice, Transgenic
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Microscopy, Electron, Transmission
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Molecular Chaperones / genetics*
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Mutation / genetics
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Neurons / metabolism*
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Neurons / pathology
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Neurons / ultrastructure
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Nuclear Envelope / metabolism*
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Nuclear Envelope / pathology
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Nuclear Envelope / ultrastructure
Substances
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Carrier Proteins
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Dyt1 protein, mouse
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HSC70 Heat-Shock Proteins
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HSPA8 protein, human
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Membrane Proteins
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Molecular Chaperones
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TOR1AIP2 protein, human