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

doi:10.1212/NXG.0000000000000626

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

Neurol Genet. 2021 Oct 1;7(6):e626. doi: 10.1212/NXG.0000000000000626. eCollection 2021 Dec.

Authors

Eiichiro Amano¹, Tomokatsu Yoshida¹, Ikuko Mizuta¹, Jun Oyama¹, Shingo Sakashita¹, Syunsuke Ueyama¹, Akira Machida¹, Takanori Yokota¹

Affiliation

¹ 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.

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.