학술논문
Identification of a novel nonsense mutation in the rod domain of GFAP that is associated with Alexander disease.
Document Type
Academic Journal
Author
Nam TS; Department of Neurology, Chonnam National University Medical School, Gwangju, Republic of Korea.; Kim JH; 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.; Chang CH; Institute of Molecular Medicine, College of Life Sciences, National Tsing Hua University, Hsinchu, Taiwan.; Yoon W; Department of Radiology, Chonnam National University Medical School, Gwangju, Republic of Korea.; Jung YS; School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.; Kang SY; Department of Neurology, College of Medicine, Jeju National University, Jeju, Republic of Korea.; Shin BA; Department of Microbiology, Chonnam National University Medical School, Gwangju, Republic of Korea.; Perng MD; Institute of Molecular Medicine, College of Life Sciences, National Tsing Hua University, Hsinchu, Taiwan.; Choi SY; 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.; Kim MK; Department of Neurology, Chonnam National University Medical School, Gwangju, Republic of Korea.
Source
Publisher: Nature Publishing Group Country of Publication: England NLM ID: 9302235 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5438 (Electronic) Linking ISSN: 10184813 NLM ISO Abbreviation: Eur J Hum Genet Subsets: MEDLINE
Subject
Language
English
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.