title: De novo mutations (GAG deletion) in the DYT1 gene in two non-Jewish patients with early-onset dystonia.
abstract: The DYT1 gene recently has been cloned and shown to contain a three nucleotide (GAG) deletion responsible for most cases of autosomal dominant 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-binding protein (torsinA). Previous haplotype analysis revealed that this same deletion had arisen at least two different times in history, suggesting independent mutational events. This deletion is the only sequence change found thus far to be associated uniquely with the disease status, regardless of ethnic origin. Here we describe two patients with typical early-onset torsion dystonia of Swiss-Mennonite and non-Jewish Russian origin, respectively, that both carry this same mutation as a de novo GAG deletion. This finding proves that this 3 bp deletion in the DYT1 gene is indeed a mutation that causes early-onset torsion dystonia. The DYT1 mutation is one of the rare examples of the same recurrent mutation causing a dominantly inherited condition. The sequence surrounding the GAG deletion contains an imperfect 24 bp tandem repeat, suggesting a possible mechanism for the high frequency of this mutation.
authors.affiliation: Molecular Neurogenetics Unit, Neurology Service, Massachusetts General Hospital and Department of Neurology and Genetics, Harvard Medical School, Boston, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Klein
authors.forename: M F
authors.initials: MF
authors.lastname: Brin
authors.forename: D
authors.initials: D
authors.lastname: de Leon
authors.forename: S A
authors.initials: SA
authors.lastname: Limborska
authors.forename: I A
authors.initials: IA
authors.lastname: Ivanova-Smolenskaya
authors.forename: S B
authors.initials: SB
authors.lastname: Bressman
authors.forename: A
authors.initials: A
authors.lastname: Friedman
authors.forename: E D
authors.initials: ED
authors.lastname: Markova
authors.forename: N J
authors.initials: NJ
authors.lastname: Risch
authors.forename: X O
authors.initials: XO
authors.lastname: Breakefield
authors.forename: L J
authors.initials: LJ
authors.lastname: Ozelius
mesh_terms: D000328:Adult; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D004422:Dystonia Musculorum Deformans / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D005260:Female; D006801:Humans; D007585:Jews / Q000235:genetics; D008297:Male; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010414:Pennsylvania; D012426:Russia; D017384:Sequence Deletion; D013557:Switzerland
chemical_list: D002352:Carrier Proteins; D018832:Molecular Chaperones; C108175:TOR1A protein, human