Copyright © 2007 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 80, Issue 6, 1188-1193, 1 June 2007
doi:10.1086/518427
Report
Intragenic Cis and Trans Modification of Genetic Susceptibility in DYT1 Torsion Dystonia
Neil J. Rischa, b, 
, 
, Susan B. Bressmanc, d, Geetha Senthile and Laurie J. Ozeliuse
a Institute for Human Genetics and Department of Epidemiology and Biostatistics, University of California at San Francisco, San Francisco
b Division of Research, Kaiser Permanente, Oakland
c Department of Neurology, Beth Israel Medical Center, New York
d Departments of Neurology Bronx
e Departments of Molecular Genetics Bronx
f Albert Einstein College of Medicine, Bronx
Address for correspondence and reprints: Dr. Neil J. Risch, Institute for Human Genetics, University of California at San Francisco, 513 Parnassus Avenue, MS 0794, Room 901F HSW, San Francisco, CA 94143-0794.Abstract
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.
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