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

Laura Melchionda, Mingyan Fang, Hairong Wang, Valeria Fugnanesi, Michela Morbin, Xuanzhu Liu, Wenyan Li, Isabella Ceccherini, Laura Farina, Mario Savoiardo, Pio D'Adamo, Jianguo Zhang, Alfredo Costa, Sabrina Ravaglia, Daniele Ghezzi, Massimo Zeviani

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Article number66
JournalOrphanet Journal of Rare Diseases
Volume8
Issue number1
DOIs
Publication statusPublished - 2013

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Alexander Disease
Exome
Siblings
Motor Neuron Disease
Mutation
Genes
Protein Isoforms
Histone Deacetylases
Glial Fibrillary Acidic Protein
Disease Susceptibility
Astrocytoma
Movement Disorders
Mothers
Magnetic Resonance Imaging
Brain

ASJC Scopus subject areas

  • Medicine(all)
  • Genetics(clinical)
  • Pharmacology (medical)

Cite this

Adult-onset Alexander disease, associated with a mutation in an alternative GFAP transcript, may be phenotypically modulated by a non-neutral HDAC6 variant. / Melchionda, Laura; Fang, Mingyan; Wang, Hairong; Fugnanesi, Valeria; Morbin, Michela; Liu, Xuanzhu; Li, Wenyan; Ceccherini, Isabella; Farina, Laura; Savoiardo, Mario; D'Adamo, Pio; Zhang, Jianguo; Costa, Alfredo; Ravaglia, Sabrina; Ghezzi, Daniele; Zeviani, Massimo.

In: Orphanet Journal of Rare Diseases, Vol. 8, No. 1, 66, 2013.

Research output: Contribution to journalArticle

Melchionda, 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 2013, 'Adult-onset Alexander disease, associated with a mutation in an alternative GFAP transcript, may be phenotypically modulated by a non-neutral HDAC6 variant', Orphanet Journal of Rare Diseases, vol. 8, no. 1, 66. https://doi.org/10.1186/1750-1172-8-66
Melchionda, Laura ; Fang, Mingyan ; Wang, Hairong ; Fugnanesi, Valeria ; Morbin, Michela ; Liu, Xuanzhu ; Li, Wenyan ; Ceccherini, Isabella ; Farina, Laura ; Savoiardo, Mario ; D'Adamo, Pio ; Zhang, Jianguo ; Costa, Alfredo ; Ravaglia, Sabrina ; Ghezzi, Daniele ; Zeviani, Massimo. / Adult-onset Alexander disease, associated with a mutation in an alternative GFAP transcript, may be phenotypically modulated by a non-neutral HDAC6 variant. In: Orphanet Journal of Rare Diseases. 2013 ; Vol. 8, No. 1.
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AU - Fang, Mingyan

AU - Wang, Hairong

AU - Fugnanesi, Valeria

AU - Morbin, Michela

AU - Liu, Xuanzhu

AU - Li, Wenyan

AU - Ceccherini, Isabella

AU - Farina, Laura

AU - Savoiardo, Mario

AU - D'Adamo, Pio

AU - Zhang, Jianguo

AU - Costa, Alfredo

AU - Ravaglia, Sabrina

AU - Ghezzi, Daniele

AU - Zeviani, Massimo

PY - 2013

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