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

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Alexander disease (AxD) is a fatal astrogliopathy.
• Mutations in the glial fibrillary acidic protein (GFAP) gene are the primary cause.
• GFAP is an intermediate filament protein crucial for astrocyte function.

Observation:

• Three patients with unique GFAP mutations were studied.
• Patient 1 presented with a noncoding splice site mutation affecting exon 4.
• Patient 2 exhibited an insertion-deletion mutation at the coding region's end, revealing chimerism (mutation in buccal but not blood DNA).
• Patient 3 had a C-terminal single-base deletion causing a frameshift.

Findings:

• A noncoding mutation can lead to Alexander disease.
• Even a small fraction of altered GFAP can cause disease.
• Chimerism can occur in Alexander disease patients.

Implications:

• Genetic testing for AxD should include intronic splice site regions.
• C-terminal tagging of intermediate filaments for research may require caution.
• Understanding diverse GFAP mutations aids AxD diagnosis and pathogenesis studies.