Mutations in DYT1: extension of the phenotypic and mutational spectrum.

Abstract

Most cases of early-onset primary torsion dystonia (PTD) are caused by the same three-base pair (bp) (GAG) deletion in the DYT1 gene. Exon rearrangements are a common mutation type in other genes and have not yet been tested for in DYT1. Several lines of evidence suggest a relationship of the DYT1 gene with Parkinson disease (PD). To investigate the frequency and type of DYT1 mutations and explore the associated phenotypes in a mixed movement disorders patient cohort and in controls. The authors screened 197 patients with dystonia (generalized: n = 5; focal/segmental: n = 126; myoclonus-dystonia: n = 34; neuroleptic-induced: n = 32), 435 with PD, and 42 with various other movement disorders, along with 812 healthy controls, for small deletions in exon 5 of DYT1 and tested for exon rearrangements by quantitative, duplex PCR in 51 GAG deletion-negative dystonia cases. The GAG deletion was detected in five patients: three with early-onset PTD, one with generalized jerky or clonic dystonia, and one with generalized dystonia and additional features (developmental delay, pyramidal syndrome). A novel out-of-frame four-bp deletion (934_937delAGAG) in exon 5 of the DYT1 gene was found in a putatively healthy blood donor. No exon rearrangements were identified in DYT1. In this mixed patient sample, the GAG deletion was rare and in two out of five cases associated with an unusual phenotype. In addition, a novel DYT1 truncating mutation of unknown clinical relevance was found in a putatively unaffected individual. DYT1 exon rearrangements, however, do not seem to be associated with PTD.