Abstract
Alexander disease (AxD) is an astrogliopathy that primarily affects the white matter of the central nervous system (CNS). AxD is caused by mutations in a gene encoding GFAP (glial fibrillary acidic protein). The GFAP mutations in AxD have been reported to act in a gain-of-function manner partly because the identified mutations generate practically full-length GFAP. We found a novel nonsense mutation (c.1000 G>T, p.(Glu312Ter); also termed p.(E312*)) within a rod domain of GFAP in a 67-year-old Korean man with a history of memory impairment and leukoencephalopathy. This mutation, GFAP p.(E312*), removes part of the 2B rod domain and the whole tail domain from the GFAP. We characterized GFAP p.(E312*) using western blotting, in vitro assembly and sedimentation assay, and transient transfection of human adrenal cortex carcinoma SW13 (Vim+) cells with plasmids encoding GFAP p.(E312*). The GFAP p.(E312*) protein, either alone or in combination with wild-type GFAP, elicited self-aggregation. In addition, the assembled GFAP p.(E312*) aggregated into paracrystal-like structures, and GFAP p.(E312*) elicited more GFAP aggregation than wild-type GFAP in the human adrenal cortex carcinoma SW13 (Vim+) cells. Our findings are the first report, to the best of our knowledge, on this novel nonsense mutation of GFAP that is associated with AxD and paracrystal formation.
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Acknowledgements
We are grateful to the patient for his help and participation in the study. We thank Nan-Hee Choi for technical assistance, Seong-Min Choi for interpretation of comprehensive neuropsychological test, Hueng-Sik Choi for support, Gary Jenkins for English editing and Eun Young Choi for encouragement. This work was supported in part by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2013-R1A1A1058252), the Chonnam National University Hospital Biomedical Research Institute (CRI 12 055-21) and the National Science Council, Taiwan (99-2311-B-007-008-MY3). Tai-Seung Nam, Seok-Yong Choi and Myeong-Kyu Kim conceived the project.
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Tai-Seung Nam, Jin Hee Kim, Chi-Hsuan Chang and Yoon Seok Jung performed the experiments. Tai-Seung Nam, Sa-Yoon Kang, Woong Yoon, Boo Ahn Shin, Ming-Der Perng, Seok-Yong Choi and Myeong-Kyu Kim analyzed and interpreted the data. Tai-Seung Nam, Ming-Der Perng, Seok-Yong Choi and Myeong-Kyu Kim drafted and revised the manuscript.
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Nam, TS., Kim, J., Chang, CH. et al. Identification of a novel nonsense mutation in the rod domain of GFAP that is associated with Alexander disease. Eur J Hum Genet 23, 72–78 (2015). https://doi.org/10.1038/ejhg.2014.68
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DOI: https://doi.org/10.1038/ejhg.2014.68
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