De novo mutations (GAG deletion) in the DYT1 gene in two non-Jewish patients with early-onset dystonia

The DYT1 gene recently has been cloned and shown to contain a threenucleotide (GAG) deletion responsible for most cases of autosomal dominantearly-onset torsion dystonia. This deletion results in the loss of one of apair of glutamic acids in a conserved region of a novel ATP-binding protein(torsinA). Previous haplotype analysis revealed that this same deletion hadarisen at least two different times in history, suggesting independentmutational events. This deletion is the only sequence change found thus farto be associated uniquely with the disease status, regardless of ethnicorigin. Here we describe two patients with typical early-onset torsiondystonia of Swiss-Mennonite and non-Jewish Russian origin, respectively,that both carry this same mutation as a de novo GAG deletion. This findingproves that this 3 bp deletion in the DYT1 gene is indeed a mutation thatcauses early-onset torsion dystonia. The DYT1 mutation is one of the rareexamples of the same recurrent mutation causing a dominantly inheritedcondition. The sequence surrounding the GAG deletion contains an imperfect24 bp tandem repeat, suggesting a possible mechanism for the high frequencyof this mutation.