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-, 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. © 2013 Melchionda et al.

Adult-onset Alexander disease, associated with a mutation in an alternative GFAP transcript, may be phenotypically modulated by a non-neutral HDAC6 variant / L. Melchionda, M. Fang, H. Wang, V. Fugnanesi, M. Morbin, X. Liu, W. Li, I. Ceccherini, L. Farina, M. Savoiardo, P. D'Adamo, J. Zhang, A. Costa, S. Ravaglia, D. Ghezzi, M. Zeviani. - In: ORPHANET JOURNAL OF RARE DISEASES. - ISSN 1750-1172. - 8:1(2013 May 01). [10.1186/1750-1172-8-66]

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

D. Ghezzi
Penultimo
;
2013

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-, 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. © 2013 Melchionda et al.
age of onset; aged; alexander disease; brain stem; cells, cultured; exome; female; fibroblasts; glial fibrillary acidic protein; high-throughput nucleotide sequencing; histone deacetylases; humans; magnetic resonance imaging; male; middle aged; phenotype; mutation; medicine (all); genetics (clinical); pharmacology (medical)
Settore MED/03 - Genetica Medica
Settore BIO/11 - Biologia Molecolare
Settore MED/26 - Neurologia
1-mag-2013
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/523784
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