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Type II Alexander disease caused by splicing errors and aberrant overexpression of an uncharacterized GFAP isoform
Author(s) -
Helman Guy,
Takanohashi Asako,
Hagemann Tracy L.,
Perng Ming D.,
Walkiewicz Marzena,
Woidill Sarah,
Sase Sunetra,
Cross Zachary,
Du Yangzhu,
Zhao Ling,
Waldman Amy,
Haake Bret C.,
Fatemi Ali,
Brenner Michael,
Sherbini Omar,
Messing Albee,
Vanderver Adeline,
Simons Cas
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24008
Subject(s) - gene isoform , biology , rna splicing , glial fibrillary acidic protein , alternative splicing , downregulation and upregulation , messenger rna , gene , microbiology and biotechnology , missense mutation , intron , genetics , exon , rna , mutation , immunology , immunohistochemistry
Alexander disease results from gain‐of‐function mutations in the gene encoding glial fibrillary acidic protein (GFAP). At least eight GFAP isoforms have been described, however, the predominant alpha isoform accounts for ∼90% of GFAP protein. We describe exonic variants identified in three unrelated families with Type II Alexander disease that alter the splicing of GFAP pre‐messenger RNA (mRNA) and result in the upregulation of a previously uncharacterized GFAP lambda isoform (NM_001363846.1). Affected members of Family 1 and Family 2 shared the same missense variant, NM_001363846.1:c.1289G>A;p.(Arg430His) while in Family 3 we identified a synonymous variant in the adjacent nucleotide, NM_001363846.1:c.1290C>A;p.(Arg430Arg). Using RNA and protein analysis of brain autopsy samples, and a mini‐gene splicing reporter assay, we demonstrate both variants result in the upregulation of the lambda isoform. Our approach demonstrates the importance of characterizing the effect of GFAP variants on mRNA splicing to inform future pathophysiologic and therapeutic study for Alexander disease.