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BMC Neurol. 2017 Sep 7;17(1):175. doi: 10.1186/s12883-017-0938-7.

Aggregation-prone GFAP mutation in Alexander disease validated using a zebrafish model.

Author information

1
Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, 501-759, Republic of Korea.
2
Center for Creative Biomedical Scientists at Chonnam National University, Gwangju, Republic of Korea.
3
Department of Neurology, Chonnam National University Medical School, Gwangju, 501-759, Republic of Korea.
4
Department of Microbiology, Chonnam National University Medical School, Gwangju, Republic of Korea.
5
Department of Radiology, Chonnam National University Medical School, Gwangju, Republic of Korea.
6
Department of Biological Sciences, Sookmyung Women's University, Seoul, Republic of Korea.
7
Institute of Molecular Medicine, College of Life Sciences, National Tsing Hua University, Hsinchu, Taiwan.
8
Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, 501-759, Republic of Korea. Jihoon.Jo@chonnam.ac.kr.
9
Department of Neurology, Chonnam National University Medical School, Gwangju, 501-759, Republic of Korea. mkkim@chonnam.ac.kr.
10
Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, 501-759, Republic of Korea. zebrafish@chonnam.ac.kr.
11
Center for Creative Biomedical Scientists at Chonnam National University, Gwangju, Republic of Korea. zebrafish@chonnam.ac.kr.

Abstract

BACKGROUND:

Alexander disease (AxD) is an astrogliopathy that predominantly affects the white matter of the central nervous system (CNS), and is caused by a mutation in the gene encoding the glial fibrillary acidic protein (GFAP), an intermediate filament primarily expressed in astrocytes and ependymal cells. The main pathologic feature of AxD is the presence of Rosenthal fibers (RFs), homogeneous eosinophilic inclusions found in astrocytes. Because of difficulties in procuring patient' CNS tissues and the presence of RFs in other pathologic conditions, there is a need to develop an in vivo assay that can determine whether a mutation in the GFAP results in aggregation and is thus disease-causing.

METHODS:

We found a GFAP mutation (c.382G > A, p.Asp128Asn) in a 68-year-old man with slowly progressive gait disturbance with tendency to fall. The patient was tentatively diagnosed with AxD based on clinical and radiological findings. To develop a vertebrate model to assess the aggregation tendency of GFAP, we expressed several previously reported mutant GFAPs and p.Asp128Asn GFAP in zebrafish embryos.

RESULTS:

The most common GFAP mutations in AxD, p.Arg79Cys, p.Arg79His, p.Arg239Cys and p.Arg239His, and p.Asp128Asn induced a significantly higher number of GFAP aggregates in zebrafish embryos than wild-type GFAP.

CONCLUSIONS:

The p.Asp128Asn GFAP mutation is likely to be a disease-causing mutation. Although it needs to be tested more extensively in larger case series, the zebrafish assay system presented here would help clinicians determine whether GFAP mutations identified in putative AxD patients are disease-causing.

KEYWORDS:

Alexander disease; Astrocyte; GFAP; Glial fibrillary acidic protein; Leukodystrophy; Rosenthal fibers; Zebrafish

PMID:
28882119
PMCID:
PMC5590178
DOI:
10.1186/s12883-017-0938-7
[Indexed for MEDLINE]
Free PMC Article

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