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A novel in-frame GFAP p.E138_L148del mutation in Type II Alexander disease with atypical phenotypes


Alexander disease (AxD) is a neurodegenerative astrogliopathy caused by mutation in the glial fibrillary acidic protein (GFAP) gene. A 42-year-old Korean man presented with temporary gait disturbance and psychiatric regression after a minor head trauma in the absence of bulbar symptoms and signs. Magnetic resonance images of the brain and spinal cord showed significant atrophy of the medulla oblongata and the entire spinal cord as well as contrast-enhanced T2 hypointensity in the basal ganglia. DNA sequencing revealed a novel 33-bp in-frame deletion mutation (p.Glu138_Leu148del) within the 1B rod domain of GFAP, which was predicted to be deleterious by PROVEAN analysis. To test whether the deletion mutant is disease-causing, we performed in vitro GFAP assembly and sedimentation assays, and GFAP aggregation assays in human adrenal carcinoma SW13 (Vim) cells and rat primary astrocytes. All the assays revealed that GFAP p.Glu138_Leu148del is aggregation prone. Based on these findings, we diagnosed the patient with Type II AxD. This is a report that demonstrates the pathogenicity of InDel mutation of GFAP through functional studies. This patient’s atypical presentation as well as the discrepancy between clinical symptoms and radiologic findings may extend the scope of AxD.

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Fig. 1: Radiological and genetic profiles of the proband.
Fig. 2: GFAP p.E138_L148del is prone to aggregation in vitro.
Fig. 3: p.E138_L148del mutation aggregates GFAP in human adrenal cortex carcinoma SW13 (Vim) cells and rat primary astrocytes.

Data availability

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.


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We thank Michael Brenner for providing SW13 (Vim) cells.


This work was supported in part by grants from the Basic Science Research Program through the Chonnam National University Hospital Biomedical Research Institute (CRI15022, BCRI 19049 and BCRI 19050), and the Ministry of Science and Technology in Taiwan (109-2320-B-007-002 and 110-2320-B-007-002).

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Authors and Affiliations



TSN, MDP, and SJL conceived and designed the study. YRK and TSN enrolled the subject and collected clinicoradiologic data. TSN, SJL, YRK, KWK and MKK analyzed and interpreted the clinicoradiologic data. SHL, GC, SYC, MSJ, NHL, AWY and MDP performed functional studies. TSN, MDP and SYC supervised the study. MDP, SYC and TSN wrote the manuscript.

Corresponding authors

Correspondence to Ming-Der Perng, Seok-Yong Choi or Tai-Seung Nam.

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The authors declare no competing interests.

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This study was approved by the Institutional Review Board at Chonnam National University Hospital (CNUH-2020-018).

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The patient provided written informed consent for the publication.

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Kang, YR., Lee, SH., Lin, NH. et al. A novel in-frame GFAP p.E138_L148del mutation in Type II Alexander disease with atypical phenotypes. Eur J Hum Genet 30, 687–694 (2022).

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