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 language | English |
|---|---|
| Article number | 66 |
| Journal | Orphanet Journal of Rare Diseases |
| Volume | 8 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2013 |
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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 journal › Article
}
TY - JOUR
T1 - Adult-onset Alexander disease, associated with a mutation in an alternative GFAP transcript, may be phenotypically modulated by a non-neutral HDAC6 variant
AU - Melchionda, Laura
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
Y1 - 2013
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84876804115&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84876804115&partnerID=8YFLogxK
U2 - 10.1186/1750-1172-8-66
DO - 10.1186/1750-1172-8-66
M3 - Article
C2 - 23634874
AN - SCOPUS:84876804115
VL - 8
JO - Orphanet Journal of Rare Diseases
JF - Orphanet Journal of Rare Diseases
SN - 1750-1172
IS - 1
M1 - 66
ER -