title: Splice site, frameshift, and chimeric GFAP mutations in Alexander disease.
abstract: Alexander disease (AxD) is a usually fatal astrogliopathy primarily caused by mutations in the gene encoding glial fibrillary acidic protein (GFAP), an intermediate filament protein expressed in astrocytes. We describe three patients with unique characteristics, and whose mutations have implications for AxD diagnosis and studies of intermediate filaments. Patient 1 is the first reported case with a noncoding mutation. The patient has a splice site change producing an in-frame deletion of exon 4 in about 10% of the transcripts. Patient 2 has an insertion and deletion at the extreme end of the coding region, resulting in a short frameshift. In addition, the mutation was found in buccal DNA but not in blood DNA, making this patient the first reported chimera. Patient 3 has a single-base deletion near the C-terminal end of the protein, producing a short frameshift. These findings recommend inclusion of intronic splice site regions in genetic testing for AxD, indicate that alteration of only a small fraction of GFAP can produce disease, and provide caution against tagging intermediate filaments at their C-terminal end for cell biological investigations.
authors.affiliation: Department of Neurobiology and the Civitan International Research Center, Center for Glial Biology in Medicine, Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, AL 35294, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Flint
authors.forename: Rong
authors.initials: R
authors.lastname: Li
authors.forename: Lital S
authors.initials: LS
authors.lastname: Webster
authors.forename: Sakkubai
authors.initials: S
authors.lastname: Naidu
authors.forename: Edwin
authors.initials: E
authors.lastname: Kolodny
authors.forename: Alan
authors.initials: A
authors.lastname: Percy
authors.forename: Marjo
authors.initials: M
authors.lastname: van der Knaap
authors.forename: James M
authors.initials: JM
authors.lastname: Powers
authors.forename: John F
authors.initials: JF
authors.lastname: Mantovani
authors.forename: Josef
authors.initials: J
authors.lastname: Ekstein
authors.forename: James E
authors.initials: JE
authors.lastname: Goldman
authors.forename: Albee
authors.initials: A
authors.lastname: Messing
authors.forename: Michael
authors.initials: M
authors.lastname: Brenner
mesh_terms: D000328:Adult; D038261:Alexander Disease / Q000235:genetics*; D001253:Astrocytes / Q000378:metabolism; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D012326:RNA Splicing / Q000235:genetics*
chemical_list: D005904:Glial Fibrillary Acidic Protein