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Functional evidence implicating a novel TOR1A mutation in idiopathic, late-onset focal dystonia
  1. Nicole Calakos1,*,
  2. Viren Patel1,
  3. Melissa Gottron1,
  4. Gaofeng Wang2,
  5. Khan-Nhat Tran-Viet1,
  6. Danielle Brewington1,
  7. John L Beyer1,
  8. David C Steffens1,
  9. Ranga R Krishnan1,
  10. Stephan Zuchner2
  1. 1 Duke University Medical Center, United States;
  2. 2 University of Miami Miller School of Medicine, United States
  1. Correspondence to: Nicole Calakos, Duke University Medical Center, Box 2900, Bryan Res. Bldg., Rm. 201E, Durham, 27710, United States; nicole.calakos{at}


Background: TOR1A encodes a chaperone-like AAA-ATPase whose ΔGAG (ΔE) mutation is responsible for an early-onset, generalized dystonia syndrome. Because of the established role of the TOR1A gene in heritable generalized dystonia (DYT1), a potential genetic contribution of TOR1A to the more prevalent and diverse presentations of late-onset, focal dystonia has been suggested.

Results: A novel TOR1A missense mutation (c.613T>A, p.F205I) in a patient with late-onset, focal dystonia is reported. The mutation occurs in a highly evolutionarily conserved region encoding the AAA-ATPase domain. Expression assays revealed that expression of F205I or ΔE, but not wildtype TOR1A produced frequent intracellular inclusions.

Conclusions: We have identified a novel, rare TOR1A variant in an individual with late-onset, focal dystonia and provided evidence that the mutation impairs TOR1A function. Together these findings raise the possibility that this novel TOR1A variant may contribute to the expression of dystonia. In light of these findings, a more comprehensive genetic effort is warranted to identify the role of this and other rare TOR1A variants in the expression of late-onset, focal dystonia.

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