Biochemical and cellular analysis of human variants of the DYT1 dystonia protein, TorsinA/TOR1A

Jasmin Hettich, Scott D. Ryan, Osmar Norberto de Souza, Luís Fernando Saraiva Macedo Timmers, Shelun Tsai, Nadia A. Atai, Cintia C. da Hora, Xuan Zhang, Rashmi Kothary, Erik Snapp, Maria Ericsson, Kathrin Grundmann, Xandra O. Breakefield, Flávia C. Nery

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1101-1113
Number of pages13
JournalHuman Mutation
Issue number9
StatePublished - Sep 2014
Externally publishedYes


  • DYT1
  • Dystonia
  • ER stress
  • Endoplasmic reticulum
  • Protein secretion
  • TOR1A
  • TorsinA

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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