Candidate gene association studies aimed at identifying genetic modifiers of penetrance in DYT1 primary dystonia. S. Gavarini1, A. Clark1, D. Raymond2, A. Mitchell1, S. B. Bressman2,3, L. J. Ozelius1 1) Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY; 2) Department of Neurology, Beth Israel Medical Center, New York, NY; 3) Department of Neurology, Albert Einstein College of Medicine, Bronx, NY.
The most severe form of the inherited primary dystonia is early onset, generalized torsion dystonia. A three-base pair deletion (946delGAG) in the gene encoding torsinA (TOR1A) is responsible for most cases of the disease, but only 30-40% of mutation carriers exhibit dystonic symptoms. To date, age of onset is the single reliable factor related to the prognosis of primary dystonia. Despite the identification of the DYT1 gene, pathological changes that lead to symptoms remain unknown. D216H, a coding-sequence variation at the TOR1A locus, has been shown to contribute to the incomplete penetrance in mutant-gene carriers. However, its overall contribution to explaining reduced penetrance is modest suggesting other factors contribute to DYT1 dystonia. TOR1A is highly homologous to three other genes, TOR1B, TOR2A and TOR3A. These homologous genes may be able to compensate for some torsinA functions in non-manifesting carriers. Genes coding for protein interactors of torsinA are also strong candidates for mediating the genetic influence on penetrance. Here we report the results of an association study comparing non-manifesting versus manifesting carriers of the TOR1A mutation looking at single nucleotide polymorphisms (SNPs) within torsin-related genes and genes encoding known protein interactors of torsinA. Identification of genes influencing the penetrance of DYT1 dystonia should clarify the underlying mechanisms of the disease and provide prognostic markers that would be clinically valuable in relation to potential future pharmacological treatments.