Type II Alexander disease caused by splicing errors and aberrant overexpression of an uncharacterized GFAP isoform.
Alexander disease
aberrant splicing
leukodystrophy
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
01
12
2019
revised:
07
02
2020
accepted:
25
02
2020
pubmed:
4
3
2020
medline:
6
11
2021
entrez:
4
3
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32126152
doi: 10.1002/humu.24008
pmc: PMC7491703
mid: NIHMS1574833
doi:
Substances chimiques
GFAP protein, human
0
Glial Fibrillary Acidic Protein
0
Protein Isoforms
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1131-1137Subventions
Organisme : NICHD NIH HHS
ID : P01 HD076892
Pays : United States
Organisme : NICHD NIH HHS
ID : P50 HD103538
Pays : United States
Organisme : NINDS NIH HHS
ID : U54 NS115052
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016520
Pays : United States
Organisme : NICHD NIH HHS
ID : U54 HD090256
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2020 Wiley Periodicals, Inc.
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