Splice site, frameshift, and chimeric GFAP mutations in Alexander disease

Daniel Flint, Rong Li, Lital S. Webster, Sakkubai Naidu, Edwin Kolodny, Alan Percy, Marjo van der Knaap, James M. Powers, John F. Mantovani, Josef Ekstein, James E. Goldman, Albee Messing, Michael Brenner

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1141-1148
Number of pages8
JournalHuman mutation
Issue number7
StatePublished - Jul 2012


  • Aggregate
  • Alexander disease
  • Astrocyte
  • Chimera
  • GFAP
  • Leukodystrophy

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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