Subcellular distribution of THAP1 and alterations in the microstructure of brain white matter in DYT6 dystonia

Abstract Background Mutations in the THAP1 gene have recently been identified as the cause of DYT6 primary dystonia. However, the changes in THAP1 gene function and in the microstructure of brain white matter have not been well-characterized. Methods Four different mutations of THAP1 expression (clones F22fs71X, C54F, F25fs53X, and L180S) were transfected into HEK-293T cells. The subcellular distribution of THAP1 in each clone was identified using immunofluorescence microscopy and Western blot. Six patients who harbored these THAP1 mutations underwent diffusion tensor magnetic resonance imaging (DTI) of the brain. The fractional anisotropy (FA) and mean diffusivity (MD) were measured in twenty-four regions of interest (ROI). Results In two truncated mutations (F22fs71X and F25fs53X), the subcellular distribution of THAP1 were both in the cytoplasm and nucleus. However, the subcellular distribution was detected almost in the nucleus in two missense mutations (C54F and L180S). In the DTI maps, the average values of fractional anisotropy (FA), a measure of axonal integrity and coherence, was reduced ( p