Type II Alexander disease caused by splicing errors and aberrant overexpression of an uncharacterized GFAP isoform

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...

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Veröffentlicht in:Human mutation 2020-06, Vol.41 (6), p.1131-1137
Hauptverfasser: 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
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container_end_page 1137
container_issue 6
container_start_page 1131
container_title Human mutation
container_volume 41
creator 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
description 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. Variants in the gene encoding glial fibrillary acidic protein (GFAP) cause Alexander disease. At least eight GFAP isoforms have been described, however, the predominant alpha isoform accounts for ∼90% of GFAP protein. Using RNA and protein analysis of brain autopsy samples, and a mini‐gene splicing reporter assay, we demonstrate that some GFAP variants result in the upregulation of uncharacterized GFAP isoforms. Our approach demonstrates the importance of characterizing the effect of GFAP variants on messenger RNA splicing to inform future pathophysiologic and therapeutic study for Alexander disease.
doi_str_mv 10.1002/humu.24008
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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&gt;A;p.(Arg430His) while in Family 3 we identified a synonymous variant in the adjacent nucleotide, NM_001363846.1:c.1290C&gt;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. Variants in the gene encoding glial fibrillary acidic protein (GFAP) cause Alexander disease. At least eight GFAP isoforms have been described, however, the predominant alpha isoform accounts for ∼90% of GFAP protein. Using RNA and protein analysis of brain autopsy samples, and a mini‐gene splicing reporter assay, we demonstrate that some GFAP variants result in the upregulation of uncharacterized GFAP isoforms. 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Variants in the gene encoding glial fibrillary acidic protein (GFAP) cause Alexander disease. At least eight GFAP isoforms have been described, however, the predominant alpha isoform accounts for ∼90% of GFAP protein. Using RNA and protein analysis of brain autopsy samples, and a mini‐gene splicing reporter assay, we demonstrate that some GFAP variants result in the upregulation of uncharacterized GFAP isoforms. Our approach demonstrates the importance of characterizing the effect of GFAP variants on messenger RNA splicing to inform future pathophysiologic and therapeutic study for Alexander disease.</abstract><cop>United States</cop><pub>Hindawi Limited</pub><pmid>32126152</pmid><doi>10.1002/humu.24008</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0003-3147-8042</orcidid><orcidid>https://orcid.org/0000-0002-4784-7423</orcidid><oa>free_for_read</oa></addata></record>
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source Wiley Online Library - AutoHoldings Journals; MEDLINE
subjects aberrant splicing
Adult
Aged
Alexander disease
Alexander Disease - genetics
Alexander's disease
Autopsy
Child
Female
Glial fibrillary acidic protein
Glial Fibrillary Acidic Protein - genetics
Humans
Isoforms
leukodystrophy
Male
Middle Aged
mRNA
Mutation, Missense
Pedigree
Protein Isoforms - genetics
Proteins
RNA Splicing
Splicing
Young Adult
title Type II Alexander disease caused by splicing errors and aberrant overexpression of an uncharacterized GFAP isoform
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