Adult-onset Alexander disease, associated with a mutation in an alternative GFAP transcript, may be phenotypically modulated by a non-neutral HDAC6 variant.

TitleAdult-onset Alexander disease, associated with a mutation in an alternative GFAP transcript, may be phenotypically modulated by a non-neutral HDAC6 variant.
Publication TypeJournal Article
Year of Publication2013
AuthorsMelchionda, L, Fang, M, Wang, H, Fugnanesi, V, Morbin, M, Liu, X, Li, W, Ceccherini, I, Farina, L, Savoiardo, M, D'Adamo, P, Zhang, J, Costa, A, Ravaglia, S, Ghezzi, D, Zeviani, M
JournalOrphanet J Rare Dis
Volume8
Pagination66
Date Published2013 May 01
ISSN1750-1172
KeywordsAge of Onset, Aged, Alexander Disease, Brain Stem, Cells, Cultured, Exome, Female, Fibroblasts, Glial Fibrillary Acidic Protein, High-Throughput Nucleotide Sequencing, Histone Deacetylase 6, Histone Deacetylases, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Phenotype
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.

DOI10.1186/1750-1172-8-66
Alternate JournalOrphanet J Rare Dis
Citation Key10.1186/1750-1172-8-66
PubMed ID23634874
PubMed Central IDPMC3654953
Grant ListGGP11011 / / Telethon / Italy
GPP10005 / / Telethon / Italy