Mild functional effects of a novel GFAP mutant allele identified in a familial case of adult-onset Alexander disease

Tiziana Bachetti, Francesco Caroli, Paola Bocca, Ignazia Prigione, Pietro Balbi, Roberta Biancheri, Mirella Filocamo, Caterina Mariotti, Davide Pareyson, Roberto Ravazzolo, Isabella Ceccherini

Research output: Contribution to journalArticlepeer-review


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 αB-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.

Original languageEnglish
Pages (from-to)462-470
Number of pages9
JournalEuropean Journal of Human Genetics
Issue number4
Publication statusPublished - Apr 2008

ASJC Scopus subject areas

  • Genetics(clinical)


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