Juvenile Alexander disease with a novel mutation in glial fibrillary acidic protein gene

Abstract

Early-onset (infantile) Alexander disease is associated with mutations in the glial fibrillary acidic protein (GFAP) gene and two hot spots correlate to the severe phenotype. No molecular mechanisms have been elucidated in late-onset (juvenile) Alexander disease. The authors report a novel GFAP mutation in a patient with juvenile Alexander disease. The authors discuss similar molecular mechanisms in another intermediate filament disease and propose a possible molecular pathogenesis in juvenile Alexander disease.

Intermediate filaments: primary determinants of cell architecture and plasticity

“…Thus, it is perhaps not surprising that mutations of the homologous amino acids in keratins, desmin, GFAP, and lamins cause disease (48). According to the specific tissue localization of the proteins, mutations that affect the salt bridge in epidermal keratins lead to blistering diseases, in desmin they lead to muscular dystrophy, and in GFAP they lead to Alexander disease (57)(58)(59)(60)(61)(62)(63)(64). In contrast, mutation of lamin A arginine 377, the arginine residue that corresponds to arginine 401 in vimentin, to either leucine or histidine gives rise to limb-girdle muscular dystrophy type 1B and Emery-Dreifuss muscular dystrophy (65)(66)(67).…”

Alexander disease: putative mechanisms of an astrocytic encephalopathy

“…4). The GFAP gene was screened on the basis of neuropathological or radiological findings consistent with AXD, and mutations were found in 48 sporadic cases and 4 families [2,13,14,18,[62][63][64].…”

Alexander-disease mutation ofGFAPcauses filament disorganization and decreased solubility of GFAP

“…Many patients with Alexander disease have been found to have one of a series of mutations in the GFAP gene (Aoki et al, 2001;Brenner et al, 2001;Gorospe et al, 2002;Okamoto et al, 2002;Rodriguez et al, 2001;Sawaishi et al, 2002;Shiihara et al, 2002;Shiroma et al, 2001) (for a review, see Li et al, 2002). The predicted amino acid changes are scattered throughout the protein, but occur principally in the rod domains, which are crucial for polymerization of GFAP into filaments.…”