DE-NOVO MUTATIONS (GAG DELETION) IN THE DYT1 GENE IN 2 NON-JEWISH PATIENTS WITH EARLY-ONSET DYSTONIA

The DYT1 gene recently has been cloned and shown to contain a three nu cleotide (GAG) deletion responsible for most cases of autosomal domina nt early-onset torsion dystonia. This deletion results in the loss of one of a pair of glutamic acids in a conserved region of a novel ATP-b inding protein (torsinA). Previous haplotype analysis revealed that th is same deletion had arisen at least two different times in history, s uggesting independent mutational events. This deletion is the only seq uence change found thus far to be associated uniquely with the disease status, regardless of ethnic origin. Here we describe two patients wi th typical early-onset torsion dystonia of Swiss-Mennonite and nonJewi sh Russian origin, respectively, that both carry this same mutation as a de novo GAG deletion. This finding proves that this 3 bp deletion i n the DYT1 gene is indeed a mutation that causes early-onset torsion d ystonia. The DYT1 mutation is one of the rare examples of the same rec urrent mutation causing a dominantly inherited condition. The sequence surrounding the GAG deletion contains an imperfect 24 bp tandem repea t, suggesting a possible mechanism for the high frequency of this muta tion.