Intragenic Cis and Trans modification of genetic susceptibility in DYT1 torsion dystonia

Am J Hum Genet. 2007 Jun;80(6):1188-93. doi: 10.1086/518427. Epub 2007 Apr 27.


A GAG deletion in the DYT1 gene is a major cause of early-onset dystonia, but clinical disease expression occurs in only 30% of mutation carriers. To gain insight into genetic factors that may influence penetrance, we evaluated three DYT1 single-nucleotide polymorphisms, including D216H, a coding-sequence variation that moderates the effects of the DYT1 GAG deletion in cellular models. We tested DYT1 GAG-deletion carriers with (n=119) and without (n=113) clinical signs of dystonia and control individuals (n=197) and found the frequency of the 216H allele to be increased in GAG-deletion carriers without dystonia and to be decreased in carriers with dystonia, compared with the control individuals. Analysis of haplotypes demonstrated a highly protective effect of the H allele in trans with the GAG deletion; there was also suggestive evidence that the D216 allele in cis is required for the disease to be penetrant. Our findings establish, for the first time, a clinically relevant gene modifier of DYT1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / metabolism
  • Alleles
  • Amino Acid Substitution
  • Aspartic Acid / metabolism
  • Case-Control Studies
  • DNA Mutational Analysis
  • DNA, Intergenic*
  • Dystonia Musculorum Deformans / genetics*
  • Gene Deletion
  • Gene Frequency
  • Genetic Markers
  • Genetic Predisposition to Disease*
  • Genetic Variation
  • Glycosaminoglycans / genetics
  • Haplotypes
  • Heterozygote
  • Humans
  • Jews
  • Microsatellite Repeats
  • Molecular Chaperones / genetics*
  • Penetrance
  • Polymorphism, Single Nucleotide


  • DNA, Intergenic
  • Genetic Markers
  • Glycosaminoglycans
  • Molecular Chaperones
  • TOR1A protein, human
  • Aspartic Acid
  • Alanine