title: Intragenic Cis and Trans modification of genetic susceptibility in DYT1 torsion dystonia.
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.
authors.affiliation: Institute for Human Genetics, University of California at San Francisco, San Francisco, CA 94143, USA. rischn@humgen.ucsf.edu
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Risch
authors.forename: Susan B
authors.initials: SB
authors.lastname: Bressman
authors.forename: Geetha
authors.initials: G
authors.lastname: Senthil
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Ozelius
mesh_terms: D000409:Alanine / Q000378:metabolism; D000483:Alleles; D019943:Amino Acid Substitution; D001224:Aspartic Acid / Q000378:metabolism; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D021901:DNA, Intergenic; D004422:Dystonia Musculorum Deformans / Q000235:genetics*; D017353:Gene Deletion; D005787:Gene Frequency; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006025:Glycosaminoglycans / Q000235:genetics; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007585:Jews; D018895:Microsatellite Repeats; D018832:Molecular Chaperones / Q000235:genetics*; D019683:Penetrance; D020641:Polymorphism, Single Nucleotide
chemical_list: D021901:DNA, Intergenic; D005819:Genetic Markers; D006025:Glycosaminoglycans; D018832:Molecular Chaperones; C108175:TOR1A protein, human; D001224:Aspartic Acid; D000409:Alanine