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Functional evidence implicating a novel TOR1A mutation in idiopathic, late-onset focal dystonia
  1. Nicole Calakos1,2,3,4,
  2. Viren D Patel1,3,
  3. Melissa Gottron2,
  4. Gaofeng Wang5,
  5. Khan-Nhat Tran-Viet6,
  6. Danielle Brewington6,
  7. John L Beyer7,
  8. David C Steffens7,
  9. Ranga R Krishnan7,8,
  10. Stephan Züchner5
  1. 1Medicine/Neurology, Duke University Medical Center, Durham, North Carolina
  2. 2Neurobiology, Duke University Medical Center, Durham, North Carolina
  3. 3Center for Translational Neuroscience, Duke University Medical Center, Durham, North Carolina
  4. 4Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina
  5. 5Miami Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida
  6. 6Center for Human Genetics, Duke University Medical Center, Durham, North Carolina
  7. 7Psychiatry, Duke University Medical Center, Durham, North Carolina 8Duke-NUS Graduate Medical School, Singapore
  8. 8Duke-NUS Graduate Medical School, Singapore
  1. Correspondence to Dr. Nicole Calakos, Center for Translational Neuroscience, Box 2900, Research Dr., Duke University Medical Center, Durham, NC 27710; nicole.calakos{at}duke.edu

Abstract

Background TOR1A encodes a chaperone-like AAA-ATPase whose ΔGAG (ΔE) mutation is responsible for an early onset, generalised dystonia syndrome. Because of the established role of the TOR1A gene in heritable generalised 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 A novel, rare TOR1A variant has been identified in an individual with late onset, focal dystonia and evidence provided 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.

  • Dystonia
  • TOR1A
  • rare sequence variant
  • depression
  • molecular genetics
  • neurology
  • movement disorders (other than Parkinson's)
  • neurosciences
  • Received 31 August 2009
  • Revised 21 October 2009
  • Accepted 2 November 2009

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Footnotes

  • NC and VDP contributed equally.

  • Funding Other Funders: NIH; Bachmann Strauss Dystonia Parkinson Foundation.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Duke University Medical Center.

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