SUSCEPTIBILITY TO <i>DYT1</i> DYSTONIA IN EUROPEAN PATIENTS IS MODIFIED BY THE D216H POLYMORPHISM

Abstract

Early-onset generalized dystonia is a rare, but frequently physically severely disabling movement disorder. The majority of cases in both the Ashkenazi Jewish (AJ) and non-Jewish (NJ) population are caused by a unique mutation, a deletion of three basepairs (GAG) in the DYT1/TOR1A gene on chromosome 9q34.1 This mutation results in the loss of one of a pair of glutamic acid residues (ΔE 302/303) at the C-terminus of the encoded protein, torsinA. Symptoms of DYT1 dystonia are highly variable, ranging from mild focal dystonia, e.g., writer’s cramp, to severe generalized dystonia, even within families.2 For reasons which have remained largely obscure, penetrance for overt signs of dystonia is reduced to approximately 30–40% in both the AJ and NJ populations.3,4 Recently, the functional significance of a nonsynonymous single-nucleotide polymorphism (SNP) in exon 4 of the DYT1 gene (rs1801968, D216H) has been demonstrated in a cell culture model system. This SNP encodes either aspartic acid (D) in 88% or histidine (H) in 12% of alleles in the general population at position 216 of the torsinA protein. Cells overexpressing the torsinA-216H variant develop inclusions similar to those induced by the GAG deletion, but introducing 216H into mutant ΔE-torsinA reduces the mutant’s tendency to form inclusions.5 These data suggest that …