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

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posted on 12.11.2014, 15:44 by Angelica Vittori, Carlo Breda, Mariaelena Repici, Michael Orth, Raymund A. C. Roos, Tiago F. Outeiro, Flaviano Giorgini, Edward J. Hollox, REGISTRY investigators of the European Huntington's Disease Network
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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Citation

Human Molecular Genetics, 2014, 23 (12), pp. 3129-3137

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Biological Sciences/Department of Genetics

Version

VoR (Version of Record)

Published in

Human Molecular Genetics

Publisher

Oxford University Press (OUP)

issn

0964-6906

eissn

1460-2083

Copyright date

2014

Available date

12/11/2014

Publisher version

http://hmg.oxfordjournals.org/content/23/12/3129

Language

en

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