Subcellular distribution of THAP1 and alterations in the microstructure of brain white matter in DYT6 dystonia.
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 < 0.005) in the subgyral white matter of the sensorimotor cortex of the DYT1 carriers, comparing with controls.


CONCLUSIONS
Truncated THAP1 mutations (F22fs71X and F25fs53X) can alter the subcellular distributions, while some missense mutation (C54F and L180S) can not. The axonal integrity and coherence in the region of sensorimotor area of the brain was damaged in DYT6 dystonia.
Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, 1# Shuaifuyuan, Wangfujing Street, Beijing, PR China.
Fu Bo
FB
Cheng
Xin Hua
XH
Wan
Jia Chun
JC
Feng
Ling Yan
LY
Ma
Bo
B
Hou
Feng
F
Feng
Lin
L
Wang
Ying Mai
YM
Yang
D000328:Adult; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001921:Brain / Q000473:pathology*; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics*; D004422:Dystonia Musculorum Deformans / Q000235:genetics* / Q000473:pathology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D009413:Nerve Fibers, Myelinated / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics*; D013347:Subcellular Fractions / Q000473:pathology; D055815:Young Adult
D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C474080:THAP1 protein, human