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

[alexander disease]

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 .