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Copy-number variation of the neuronal glucose transporter gene SLC2A3 and age of onset in Huntington's disease

Huntington's disease (HD) is a devastating neurodegenerative disorder which is inherited in an autosomal dominant manner. HD is caused by a trinucleotide CAG repeat expansion that encodes a polyglutamine stretch in the huntingtin (HTT) protein. Mutant HTT expression leads to a myriad of cellula...

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Autores principales: Vittori, Angelica, Breda, Carlo, Repici, Mariaelena, Orth, Michael, Roos, Raymund A.C., Outeiro, Tiago F., Giorgini, Flaviano, Hollox, Edward J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030768/
https://www.ncbi.nlm.nih.gov/pubmed/24452335
http://dx.doi.org/10.1093/hmg/ddu022
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author Vittori, Angelica
Breda, Carlo
Repici, Mariaelena
Orth, Michael
Roos, Raymund A.C.
Outeiro, Tiago F.
Giorgini, Flaviano
Hollox, Edward J.
author_facet Vittori, Angelica
Breda, Carlo
Repici, Mariaelena
Orth, Michael
Roos, Raymund A.C.
Outeiro, Tiago F.
Giorgini, Flaviano
Hollox, Edward J.
author_sort Vittori, Angelica
collection PubMed
description Huntington's disease (HD) is a devastating neurodegenerative disorder which is inherited in an autosomal dominant manner. HD is caused by a trinucleotide CAG repeat expansion that encodes a polyglutamine stretch in the huntingtin (HTT) protein. Mutant HTT expression leads to a myriad of cellular dysfunctions culminating in neuronal loss and consequent motor, cognitive and psychiatric disturbances in HD patients. The length of the CAG repeat is inversely correlated with age of onset (AO) in HD patients, while environmental and genetic factors can further modulate this parameter. Here, we explored whether the recently described copy-number variation (CNV) of the gene SLC2A3—which encodes the neuronal glucose transporter GLUT3—could modulate AO in HD. Strikingly, we found that increased dosage of SLC2A3 delayed AO in an HD cohort of 987 individuals, and that this correlated with increased levels of GLUT3 in HD patient cells. To our knowledge this is the first time that CNV of a candidate gene has been found to modulate HD pathogenesis. Furthermore, we found that increasing dosage of Glut1—the Drosophila melanogaster homologue of this glucose transporter—ameliorated HD-relevant phenotypes in fruit flies, including neurodegeneration and life expectancy. As alterations in glucose metabolism have been implicated in HD pathogenesis, this study may have important therapeutic relevance for HD.
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spelling pubmed-40307682014-05-28 Copy-number variation of the neuronal glucose transporter gene SLC2A3 and age of onset in Huntington's disease Vittori, Angelica Breda, Carlo Repici, Mariaelena Orth, Michael Roos, Raymund A.C. Outeiro, Tiago F. Giorgini, Flaviano Hollox, Edward J. Hum Mol Genet Articles Huntington's disease (HD) is a devastating neurodegenerative disorder which is inherited in an autosomal dominant manner. HD is caused by a trinucleotide CAG repeat expansion that encodes a polyglutamine stretch in the huntingtin (HTT) protein. Mutant HTT expression leads to a myriad of cellular dysfunctions culminating in neuronal loss and consequent motor, cognitive and psychiatric disturbances in HD patients. The length of the CAG repeat is inversely correlated with age of onset (AO) in HD patients, while environmental and genetic factors can further modulate this parameter. Here, we explored whether the recently described copy-number variation (CNV) of the gene SLC2A3—which encodes the neuronal glucose transporter GLUT3—could modulate AO in HD. Strikingly, we found that increased dosage of SLC2A3 delayed AO in an HD cohort of 987 individuals, and that this correlated with increased levels of GLUT3 in HD patient cells. To our knowledge this is the first time that CNV of a candidate gene has been found to modulate HD pathogenesis. Furthermore, we found that increasing dosage of Glut1—the Drosophila melanogaster homologue of this glucose transporter—ameliorated HD-relevant phenotypes in fruit flies, including neurodegeneration and life expectancy. As alterations in glucose metabolism have been implicated in HD pathogenesis, this study may have important therapeutic relevance for HD. Oxford University Press 2014-06-15 2014-01-22 /pmc/articles/PMC4030768/ /pubmed/24452335 http://dx.doi.org/10.1093/hmg/ddu022 Text en © The Author 2014. Published by Oxford University Press. http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Vittori, Angelica
Breda, Carlo
Repici, Mariaelena
Orth, Michael
Roos, Raymund A.C.
Outeiro, Tiago F.
Giorgini, Flaviano
Hollox, Edward J.
Copy-number variation of the neuronal glucose transporter gene SLC2A3 and age of onset in Huntington's disease
title Copy-number variation of the neuronal glucose transporter gene SLC2A3 and age of onset in Huntington's disease
title_full Copy-number variation of the neuronal glucose transporter gene SLC2A3 and age of onset in Huntington's disease
title_fullStr Copy-number variation of the neuronal glucose transporter gene SLC2A3 and age of onset in Huntington's disease
title_full_unstemmed Copy-number variation of the neuronal glucose transporter gene SLC2A3 and age of onset in Huntington's disease
title_short Copy-number variation of the neuronal glucose transporter gene SLC2A3 and age of onset in Huntington's disease
title_sort copy-number variation of the neuronal glucose transporter gene slc2a3 and age of onset in huntington's disease
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030768/
https://www.ncbi.nlm.nih.gov/pubmed/24452335
http://dx.doi.org/10.1093/hmg/ddu022
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