Inhibition of N-linked glycosylation prevents inclusion formation by the dystonia-related mutant form of torsinA.

Most cases of early-onset torsion dystonia are associated with a mutation in the DYT1 gene that results in the loss of a glutamic acid residue in the carboxy terminus of the encoded protein, torsinA. When overexpressed in cultured cells, wild-type torsinA distributes diffusely throughout the endoplasmic reticulum (ER), while the dystonia-related mutant, torsinADeltaE, accumulates within multilamellar membrane inclusions. Here we show that inclusion formation requires the addition of an N-linked oligosaccharide to one of two asparagine residues within the ATP-binding domain of the mutant protein. In the absence of this modification, overexpressed torsinADeltaE was localized diffusely throughout the cell in a reticular pattern resembling that of wild-type torsinA. In contrast, the localization of wild-type torsinA did not appear to vary with its glycosylation state. These results thus indicate that torsinADeltaE must achieve a specific conformation to induce formation of intracellular membrane inclusions.