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

European Journal of Human Genetics : EJHG
Tiziana BachettiI Ceccherini

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 ...Continue Reading

References

Jul 1, 1976·Neurology·L S RussoP J Anderson
May 18, 1999·The American Journal of Pathology·Y Koyama, J E Goldman
Aug 14, 1999·The Journal of Biological Chemistry·C EliassonM Pekny
Oct 7, 2004·Journal of the Neurological Sciences·Takashi ShiiharaKiyoshi Hayasaka
Apr 21, 2005·Journal of Cell Science·Victoria C HsiaoJames E Goldman
Oct 19, 2006·The International Journal of Biochemistry & Cell Biology·Tiziana BachettiIsabella Ceccherini
Nov 16, 2007·Journal of Neurology·Pietro BalbiLucio Santoro

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Citations

Oct 1, 2010·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Albee MessingTracy L Hagemann
Aug 8, 2008·Brain : a Journal of Neurology·Davide PareysonMario Savoiardo
Oct 14, 2009·International Journal of Developmental Neuroscience : the Official Journal of the International Society for Developmental Neuroscience·Samanta Oliveira LoureiroRegina Pessoa-Pureur
Apr 21, 2019·Journal of Medical Genetics·Carlos CasasnovasAurora Pujol
May 29, 2021·Neurogenetics·Camille K HuntJemeen Sreedharan

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