Novel deletion mutation in GFAP gene in an infantile form of Alexander disease.

Alexander disease is a rare, fatal neurologic disorder characterized by white-matter degeneration and cytoplasmic inclusions in astrocytes known as Rosenthal fibers, which are immunohistochemically positive to glial fibrillary acidic protein. Mutations in the glial fibrillary acidic protein gene were reported in patients with Alexander disease who had clinical and pathologic characteristics of the disease. All reported cases manifest heterozygous missense mutations, except for some insertions or deletions with no frame shift. Our patient had a heterozygous deletion of genomic sequence 1247-1249GGG>GG in exon 8 of the glial fibrillary acidic protein gene, which leads to a frame shift changing 16 amino acids and inducing a stop codon at codon 431 of 432 codons. The deletion mutation induces a structural conformation change in glial fibrillary acidic protein and their abnormal aggregation in astrocytes. This is the first report of a novel deletion mutation in the glial fibrillary acidic protein gene with a frame shift associated with Alexander disease.