title: Adult-onset Alexander disease, associated with a mutation in an alternative GFAP transcript, may be phenotypically modulated by a non-neutral HDAC6 variant.
abstract: BACKGROUND
  We studied a family including two half-siblings, sharing the same mother, affected by slowly progressive, adult-onset neurological syndromes. In spite of the diversity of the clinical features, characterized by a mild movement disorder with cognitive impairment in the elder patient, and severe motor-neuron disease (MND) in her half-brother, the brain Magnetic Resonance Imaging (MRI) features were compatible with adult-onset Alexander's disease (AOAD), suggesting different expression of the same, genetically determined, condition.
  
  
  METHODS
  Since mutations in the alpha isoform of glial fibrillary acidic protein, GFAP-α, the only cause so far known of AOAD, were excluded, we applied exome Next Generation Sequencing (NGS) to identify gene variants, which were then functionally validated by molecular characterization of recombinant and patient-derived cells.
  
  
  RESULTS
  Exome-NGS revealed a mutation in a previously neglected GFAP isoform, GFAP-ϵ, which disrupts the GFAP-associated filamentous cytoskeletal meshwork of astrocytoma cells. To shed light on the different clinical features in the two patients, we sought for variants in other genes. The male patient had a mutation, absent in his half-sister, in X-linked histone deacetylase 6, a candidate MND susceptibility gene.
  
  
  CONCLUSIONS
  Exome-NGS is an unbiased approach that not only helps identify new disease genes, but may also contribute to elucidate phenotypic expression.
authors: Unit of Molecular Neurogenetics, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.
authors: Laura
authors: L
authors: Melchionda
authors: Mingyan
authors: M
authors: Fang
authors: Hairong
authors: H
authors: Wang
authors: Valeria
authors: V
authors: Fugnanesi
authors: Michela
authors: M
authors: Morbin
authors: Xuanzhu
authors: X
authors: Liu
authors: Wenyan
authors: W
authors: Li
authors: Isabella
authors: I
authors: Ceccherini
authors: Laura
authors: L
authors: Farina
authors: Mario
authors: M
authors: Savoiardo
authors: Pio
authors: P
authors: D'Adamo
authors: Jianguo
authors: J
authors: Zhang
authors: Alfredo
authors: A
authors: Costa
authors: Sabrina
authors: S
authors: Ravaglia
authors: Daniele
authors: D
authors: Ghezzi
authors: Massimo
authors: M
authors: Zeviani
mesh_terms: D017668:Age of Onset; D000368:Aged; D038261:Alexander Disease / Q000235:genetics* / Q000473:pathology*; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D059472:Exome; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype
chemical_list: D005904:Glial Fibrillary Acidic Protein; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
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