DYT6 Protein Interacts with DYT1 Gene

Subject: DYT6 Protein Interacts with DYT1 Gene

Date: 11/4/2010

The protein encoded by DYT6 links to the promoter of the DYT1 gene, according to a new study. The two genes are the only genes identified as causes of primary dystonia. DYT1 is also known as TOR1A, and DYT6 as THAP1.

THAP1 encodes a DNA-binding protein with multiple targets. To determine if THAP1 targets TOR1A, the authors purified nuclear extracts of cells transfected with human wild-type THAP1 and exposed the extract to a fragment of the TOR1A gene. The THAP1 protein bound to the gene, an effect that was prevented by mutation of either THAP1 or TOR1A. The interaction was confirmed in vivo in cell culture.

In cells, the reduction in DNA binding due to THAP1 mutation occurred both when the DNA binding sequence was mutated, and when the nuclear localization sequence was mutated. The authors note, “The different THAP1 mutations described in dystonia type 6 patients, which affect either the DNA-binding domain or remove the NLS, have the same functional consequence, i.e. the abrogation of THAP1 binding to TOR1A in vivo. This may explain the lack of genotype–phenotype correlations in dystonia type 6 patients to date.”

Analysis of TOR1A expression in lymphoblasts derived from DYT6 patients, and THAP1 in fibroblasts from DYT1 patients, did not reveal any change in expression compared to controls. The lack of effect may be due to the specificity of the THAP1-TOR1A interaction by brain region or developmental stage, the authors suggest.

“The present study offers important new insights into molecular mechanisms of primary dystonia pathogenesis and raises the possibility that novel therapeutics targeting this common pathway may be effective for the treatment of different forms of dystonia,” they conclude.

Direct interaction between causative genes of DYT1 andDYT6 primary dystonia
S Gavarini, C Cayrol, T Fuchs, N Lyons, ME Erlich, J-P Girard, LJ Ozelius
Ann Neurol 2010;68:549-553.