title: Loss of the dystonia-associated protein torsinA selectively disrupts the neuronal nuclear envelope.
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.
authors.affiliation: Department of Neurology, Columbia University, New York, New York 10032, USA.
authors.forename: Rose E
authors.initials: RE
authors.lastname: Goodchild
authors.forename: Connie Eunji
authors.initials: CE
authors.lastname: Kim
authors.forename: William T
authors.initials: WT
authors.lastname: Dauer
mesh_terms: D000818:Animals; D001921:Brain / Q000002:abnormalities* / Q000378:metabolism* / Q000503:physiopathology; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004422:Dystonia Musculorum Deformans / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D018832:Molecular Chaperones / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009685:Nuclear Envelope / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure
chemical_list: D002352:Carrier Proteins; C491548:Dyt1 protein, mouse; D050883:HSC70 Heat-Shock Proteins; C494371:HSPA8 protein, human; D008565:Membrane Proteins; D018832:Molecular Chaperones; C500006:TOR1AIP2 protein, human