Toward therapy for DYT1 dystonia: allele-specific silencing of mutant TorsinA

Ann Neurol. 2003 Jun;53(6):781-7. doi: 10.1002/ana.10548.


A three-nucleotide (GAG) deletion in the TOR1A gene is the most common cause of inherited dystonia, DYT1. Because the mutant protein, TorsinA (TA), is thought to act in a dominant manner to cause disease, inhibiting expression from the mutant gene represents a potentially powerful therapeutic strategy. In an effort to develop therapy for this disease, we tested whether small interfering RNA (siRNA) could selectively silence expression of mutant TA. Exploiting the three-base pair difference between wild-type and mutant alleles, we designed siRNAs to silence expression of mutant, wild-type, or both forms of TA. In transfected cells, siRNA successfully suppressed wild-type or mutant TA in an allele-specific manner: for example, mutant-specific siRNA reduced the levels of mutant TA to less than 1% of controls with minimal effect on wild-type TA expression. In cells expressing both alleles, thus simulating the heterozygous state, siRNA-mediated suppression remained robust and allele specific. Our siRNA studies demonstrate allele-specific targeting of a dominant neurogenetic disease gene and suggest the broad therapeutic potential of siRNA for DYT1 dystonia and other dominantly inherited neurological diseases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles*
  • Blotting, Western
  • Carrier Proteins / genetics*
  • Cell Culture Techniques
  • Dystonia / genetics*
  • Dystonia / therapy*
  • Gene Deletion
  • Gene Silencing*
  • Genetic Therapy / methods*
  • Humans
  • Microscopy, Fluorescence
  • Molecular Chaperones*
  • Plasmids / genetics
  • Point Mutation / genetics*
  • RNA, Small Interfering / genetics*
  • Transfection / methods


  • Carrier Proteins
  • Molecular Chaperones
  • RNA, Small Interfering
  • TOR1A protein, human