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

Abstract

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.

• Authors: Guy Helman, Asako Takanohashi, Tracy L Hagemann, Ming D Perng, Marzena Walkiewicz, Sarah Woidill, Sunetra Sase, Zachary Cross, Yangzhu Du, Ling Zhao, Amy Waldman, Bret C Haake, Ali Fatemi, Michael Brenner, Omar Sherbini, Albee Messing, Adeline Vanderver, Cas Simons
• Journal: Human mutation (Hum Mutat) Vol. 41 Issue 6 Pg. 1131-1137 (06 2020) ISSN: 1098-1004 [Electronic] United States
• PMID: 32126152 (Publication Type: 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.)
• Copyright: © 2020 Wiley Periodicals, Inc.

Chemical References

• GFAP protein, human
• Glial Fibrillary Acidic Protein
• Protein Isoforms

Topics

• Adult
• Aged
• Alexander Disease (genetics)
• Child
• Female
• Glial Fibrillary Acidic Protein (genetics)
• Humans
• Male
• Middle Aged
• Mutation, Missense
• Pedigree
• Protein Isoforms (genetics)
• RNA Splicing
• Young Adult