Intragenic Cis and Trans modification of genetic susceptibility in DYT1 torsion dystonia.
Am J Hum Genet
; 80(6): 1188-93, 2007 Jun.
Article
in En
| MEDLINE
| ID: mdl-17503336
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Molecular Chaperones
/
Genetic Predisposition to Disease
/
DNA, Intergenic
/
Dystonia Musculorum Deformans
Type of study:
Observational_studies
/
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Am J Hum Genet
Year:
2007
Document type:
Article
Affiliation country:
United States