title: Identification of a novel nonsense mutation in the rod domain of GFAP that is associated with Alexander disease.
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.
authors.affiliation: Department of Neurology, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Tai-Seung
authors.initials: TS
authors.lastname: Nam
authors.affiliation: 1] Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea [2] Department of Microbiology, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Institute of Molecular Medicine, College of Life Sciences, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Chi-Hsuan
authors.initials: CH
authors.lastname: Chang
authors.affiliation: Department of Radiology, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Woong
authors.initials: W
authors.lastname: Yoon
authors.affiliation: School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Yoon Seok
authors.initials: YS
authors.lastname: Jung
authors.affiliation: Department of Neurology, College of Medicine, Jeju National University, Jeju, Republic of Korea.
authors.forename: Sa-Yoon
authors.initials: SY
authors.lastname: Kang
authors.affiliation: Department of Microbiology, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Boo Ahn
authors.initials: BA
authors.lastname: Shin
authors.affiliation: Institute of Molecular Medicine, College of Life Sciences, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Ming-Der
authors.initials: MD
authors.lastname: Perng
authors.affiliation: 1] Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea [2] School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Seok-Yong
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Department of Neurology, Chonnam National University Medical School, Gwangju, Republic of Korea.
authors.forename: Myeong-Kyu
authors.initials: MK
authors.lastname: Kim
mesh_terms: D000368:Aged; D038261:Alexander Disease / Q000175:diagnosis* / Q000235:genetics*; D001921:Brain / Q000473:pathology; D002460:Cell Line; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D015870:Gene Expression; D005904:Glial Fibrillary Acidic Protein / Q000737:chemistry / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D010641:Phenotype; D066263:Protein Aggregation, Pathological; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D005904:Glial Fibrillary Acidic Protein
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