Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 80, Issue 6, Pages 1188-1193Publisher
CELL PRESS
DOI: 10.1086/518427
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Funding
- NINDS NIH HHS [NS26656, P01 NS037409, NS37409, R01 NS026656, NS38142] Funding Source: Medline
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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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