title: Biochemical and cellular analysis of human variants of the DYT1 dystonia protein, TorsinA/TOR1A.
abstract: Early-onset dystonia is associated with the deletion of one of a pair of glutamic acid residues (c.904_906delGAG/c.907_909delGAG; p.Glu302del/Glu303del; ΔE 302/303) near the carboxyl-terminus of torsinA, a member of the AAA(+) protein family that localizes to the endoplasmic reticulum lumen and nuclear envelope. This deletion commonly underlies early-onset DYT1 dystonia. While the role of the disease-causing mutation, torsinAΔE, has been established through genetic association studies, it is much less clear whether other rare human variants of torsinA are pathogenic. Two missense variations have been described in single patients: R288Q (c.863G>A; p.Arg288Gln; R288Q) identified in a patient with onset of severe generalized dystonia and myoclonus since infancy and F205I (c.613T>A, p.Phe205Ile; F205I) in a psychiatric patient with late-onset focal dystonia. In this study, we have undertaken a series of analyses comparing the biochemical and cellular effects of these rare variants to torsinAΔE and wild-type (wt) torsinA to reveal whether there are common dysfunctional features. The results revealed that the variants, R288Q and F205I, are more similar in their properties to torsinAΔE protein than to torsinAwt. These findings provide functional evidence for the potential pathogenic nature of these rare sequence variants in the TOR1A gene, thus implicating these pathologies in the development of dystonia.
authors.affiliation: Molecular Neurogenetics Unit, Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts; Department of Medical Genetics and Applied Genomics, University of Tuebingen, Tübingen, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Hettich
authors.forename: Scott D
authors.initials: SD
authors.lastname: Ryan
authors.forename: Osmar Norberto
authors.initials: ON
authors.lastname: de Souza
authors.forename: Luís Fernando
authors.initials: LF
authors.lastname: Saraiva Macedo Timmers
authors.forename: Shelun
authors.initials: S
authors.lastname: Tsai
authors.forename: Nadia A
authors.initials: NA
authors.lastname: Atai
authors.forename: Cintia C
authors.initials: CC
authors.lastname: da Hora
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kothary
authors.forename: Erik
authors.initials: E
authors.lastname: Snapp
authors.forename: Maria
authors.initials: M
authors.lastname: Ericsson
authors.forename: Kathrin
authors.initials: K
authors.lastname: Grundmann
authors.forename: Xandra O
authors.initials: XO
authors.lastname: Breakefield
authors.forename: Flávia C
authors.initials: FC
authors.lastname: Nery
mesh_terms: D004422:Dystonia Musculorum Deformans / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D055785:Gene Knockdown Techniques; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010641:Phenotype; D011487:Protein Conformation; D055503:Protein Multimerization; D021381:Protein Transport; D014759:Viral Envelope Proteins / Q000378:metabolism
chemical_list: D018832:Molecular Chaperones; C108175:TOR1A protein, human; D014759:Viral Envelope Proteins
keywords: DYT1; ER stress; TOR1A; dystonia; endoplasmic reticulum; protein secretion; torsinA