Intragenic Cis and Trans Modification of Genetic Susceptibility in DYT1 Torsion Dystonia

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2007 May 16

PMID 17503336

Citations 50

Authors

Neil J Risch

Susan B Bressman

Geetha Senthil

Laurie J Ozelius

Affiliations

Soon will be listed here.

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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