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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)3129-3137
Number of pages9
JournalHuman Molecular Genetics
Volume23
Issue number12
DOIs
Publication statusPublished - 15 Jun 2014

Bibliographical note

© The Author 2014. Published by Oxford University Press.
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.

Keywords

  • Age of Onset
  • Animals
  • Cell Line
  • Cohort Studies
  • DNA Copy Number Variations
  • Disease Models, Animal
  • Drosophila Proteins/genetics
  • Drosophila melanogaster/metabolism
  • Female
  • Gene Dosage
  • Glucose Transporter Type 3/genetics
  • Humans
  • Huntington Disease/epidemiology
  • Male
  • Phylogeny
  • Up-Regulation

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