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Neurology Genetics
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December 2021; 7 (6) Clinical/Scientific NotesOpen Access

Activation of a Cryptic Splice Site of GFAP in a Patient With Adult-Onset Alexander Disease

View ORCID ProfileEiichiro Amano, View ORCID ProfileTomokatsu Yoshida, View ORCID ProfileIkuko Mizuta, View ORCID ProfileJun Oyama, View ORCID ProfileShingo Sakashita, Syunsuke Ueyama, View ORCID ProfileAkira Machida, View ORCID ProfileTakanori Yokota
First published October 1, 2021, DOI: https://doi.org/10.1212/NXG.0000000000000626
Eiichiro Amano
From the Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (E.A., T. Yokota); Department of Neurology, Tsuchiura Kyodo General Hospital (E.A., A.M.), Ibaraki; Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine (T. Yoshida, I.M.); Department of Radiology, Tokyo Medical and Dental University (J.O.); Department of Pathology, Tsuchiura Kyodo General Hospital (S.S.), Ibaraki; Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center (S.S.), Chiba; and Department of Gastroenterology, Tsuchiura Kyodo General Hospital (S.U.), Ibaraki, Japan.
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  • ORCID record for Eiichiro Amano
Tomokatsu Yoshida
From the Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (E.A., T. Yokota); Department of Neurology, Tsuchiura Kyodo General Hospital (E.A., A.M.), Ibaraki; Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine (T. Yoshida, I.M.); Department of Radiology, Tokyo Medical and Dental University (J.O.); Department of Pathology, Tsuchiura Kyodo General Hospital (S.S.), Ibaraki; Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center (S.S.), Chiba; and Department of Gastroenterology, Tsuchiura Kyodo General Hospital (S.U.), Ibaraki, Japan.
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  • For correspondence: toyoshid@koto.kpu-m.ac.jp
Ikuko Mizuta
From the Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (E.A., T. Yokota); Department of Neurology, Tsuchiura Kyodo General Hospital (E.A., A.M.), Ibaraki; Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine (T. Yoshida, I.M.); Department of Radiology, Tokyo Medical and Dental University (J.O.); Department of Pathology, Tsuchiura Kyodo General Hospital (S.S.), Ibaraki; Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center (S.S.), Chiba; and Department of Gastroenterology, Tsuchiura Kyodo General Hospital (S.U.), Ibaraki, Japan.
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  • For correspondence: imizuta@koto.kpu-m.ac.jp
Jun Oyama
From the Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (E.A., T. Yokota); Department of Neurology, Tsuchiura Kyodo General Hospital (E.A., A.M.), Ibaraki; Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine (T. Yoshida, I.M.); Department of Radiology, Tokyo Medical and Dental University (J.O.); Department of Pathology, Tsuchiura Kyodo General Hospital (S.S.), Ibaraki; Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center (S.S.), Chiba; and Department of Gastroenterology, Tsuchiura Kyodo General Hospital (S.U.), Ibaraki, Japan.
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  • For correspondence: junoym@gmail.com
Shingo Sakashita
From the Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (E.A., T. Yokota); Department of Neurology, Tsuchiura Kyodo General Hospital (E.A., A.M.), Ibaraki; Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine (T. Yoshida, I.M.); Department of Radiology, Tokyo Medical and Dental University (J.O.); Department of Pathology, Tsuchiura Kyodo General Hospital (S.S.), Ibaraki; Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center (S.S.), Chiba; and Department of Gastroenterology, Tsuchiura Kyodo General Hospital (S.U.), Ibaraki, Japan.
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  • For correspondence: sakashingo@hotmail.com
Syunsuke Ueyama
From the Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (E.A., T. Yokota); Department of Neurology, Tsuchiura Kyodo General Hospital (E.A., A.M.), Ibaraki; Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine (T. Yoshida, I.M.); Department of Radiology, Tokyo Medical and Dental University (J.O.); Department of Pathology, Tsuchiura Kyodo General Hospital (S.S.), Ibaraki; Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center (S.S.), Chiba; and Department of Gastroenterology, Tsuchiura Kyodo General Hospital (S.U.), Ibaraki, Japan.
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  • For correspondence: ueyama2113@tkgh.jp
Akira Machida
From the Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (E.A., T. Yokota); Department of Neurology, Tsuchiura Kyodo General Hospital (E.A., A.M.), Ibaraki; Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine (T. Yoshida, I.M.); Department of Radiology, Tokyo Medical and Dental University (J.O.); Department of Pathology, Tsuchiura Kyodo General Hospital (S.S.), Ibaraki; Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center (S.S.), Chiba; and Department of Gastroenterology, Tsuchiura Kyodo General Hospital (S.U.), Ibaraki, Japan.
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  • For correspondence: akinuro@tmd.ac.jp
Takanori Yokota
From the Department of Neurology and Neurological Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (E.A., T. Yokota); Department of Neurology, Tsuchiura Kyodo General Hospital (E.A., A.M.), Ibaraki; Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine (T. Yoshida, I.M.); Department of Radiology, Tokyo Medical and Dental University (J.O.); Department of Pathology, Tsuchiura Kyodo General Hospital (S.S.), Ibaraki; Division of Pathology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center (S.S.), Chiba; and Department of Gastroenterology, Tsuchiura Kyodo General Hospital (S.U.), Ibaraki, Japan.
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  • For correspondence: tak-yokota.nuro@tmd.ac.jp
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Citation
Activation of a Cryptic Splice Site of GFAP in a Patient With Adult-Onset Alexander Disease
Eiichiro Amano, Tomokatsu Yoshida, Ikuko Mizuta, Jun Oyama, Shingo Sakashita, Syunsuke Ueyama, Akira Machida, Takanori Yokota
Neurol Genet Dec 2021, 7 (6) e626; DOI: 10.1212/NXG.0000000000000626

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Abstract

Background and Objective Alexander disease (ALXDRD) is an autosomal dominant neurologic disorder caused by mutations in the glial fibrillary acidic protein (GFAP) gene and is pathologically defined by Rosenthal fiber accumulation. Most mutations are exonic missense mutations, and splice site mutations are rare. We report a very-late-onset autopsied case of adult-onset ALXDRD with a novel splice site mutation.

Methods Genetic testing of GFAP was performed by Sanger sequencing. Using autopsied brain tissues, GFAP transcript analysis was performed.

Results The patient presented mild upper motor neuron symptoms in contrast to the severe atrophy of spinal cord and medulla oblongata. The patient had c.619-1G>A mutation, which is located in the canonical splice acceptor site of intron 3. The brain RNA analysis identified the r.619_621del (p.Glu207del) mutation, which is explained by the activation of the cryptic splice acceptor site in the second and third nucleotides from the 5′ end of the exon 4.

Discussion GFAP gene expression analysis is necessary to clarify the effects of intronic mutations on splicing, even if they are in canonical splice sites. This case showed a much milder phenotype than those in previous cases with missense mutations at Glu207, thereby expanding the clinical spectrum of ALXDRD with Glu207 mutation.

Footnotes

  • Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article

  • The Article Processing Charge was funded by the authors.

  • Received May 31, 2021.
  • Accepted in final form August 13, 2021.
  • Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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