title: Mild functional effects of a novel GFAP mutant allele identified in a familial case of adult-onset Alexander disease.
abstract: Alexander disease is a neurological genetic disorder characterized by progressive white-matter degeneration, with astrocytes containing cytoplasmic aggregates, called Rosenthal fibers, including the intermediate filament glial fibrillary acidic protein (GFAP). The age of onset of the disease defines three different forms, infantile, juvenile and adult, all due to heterozygous GFAP mutations and characterized by a progressive less severe phenotype from infantile to adult forms. In an Italian family with a recurrent mild adult onset of Alexander disease, we have identified two GFAP mutations, coupled on a same allele, leading to p.[R330G; E332K]. Functional studies on this complex allele revealed less severe aggregation patterns compared to those observed with p.R239C GFAP mutant, associated with a severe Alexander disease phenotype. Moreover, in addition to confirming the involvement of the ubiquitin-proteasome system in cleaning cells from aggregates and a dominant effect of the novel mutant protein, in cells expressing the mild p.[R330G; E332K] mutant we have observed that indirect alphaB-crystallin overexpression, induced by high extracellular potassium concentration, could completely rescue the correct filament organization while, under the same experimental conditions, in cells expressing the severe p.R239C mutant only a partial rescue effect could be achieved.
authors.affiliation: Laboratory of Molecular Genetics, G Gaslini Institute, Genoa, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Bachetti
authors.forename: Francesco
authors.initials: F
authors.lastname: Caroli
authors.forename: Paola
authors.initials: P
authors.lastname: Bocca
authors.forename: Ignazia
authors.initials: I
authors.lastname: Prigione
authors.forename: Pietro
authors.initials: P
authors.lastname: Balbi
authors.forename: Roberta
authors.initials: R
authors.lastname: Biancheri
authors.forename: Mirella
authors.initials: M
authors.lastname: Filocamo
authors.forename: Caterina
authors.initials: C
authors.lastname: Mariotti
authors.forename: Davide
authors.initials: D
authors.lastname: Pareyson
authors.forename: Roberto
authors.initials: R
authors.lastname: Ravazzolo
authors.forename: Isabella
authors.initials: I
authors.lastname: Ceccherini
mesh_terms: D000328:Adult; D017668:Age of Onset; D038261:Alexander Disease / Q000235:genetics* / Q000503:physiopathology; D000483:Alleles; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics* / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D025801:Ubiquitin / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism; D038203:alpha-Crystallin B Chain / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D025801:Ubiquitin; D014746:Vimentin; D038203:alpha-Crystallin B Chain; D049452:Green Fluorescent Proteins