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

Lookup NU author(s): Professor Tiago OuteiroORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

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 thehuntingtin(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.Further more,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. ©The Author 2014.Published by Oxford University Press.

Publication metadata

Author(s): Vittori A, Breda C, Repici M, Orth M, Roos RAC, Outeiro TF, Giorgini F, Hollox EJ

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2014

Volume: 23

Issue: 12

Pages: 3129-3137

Print publication date: 15/06/2014

Online publication date: 22/01/2014

Acceptance date: 19/01/2014

Date deposited: 19/12/2017

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press

URL: https://doi.org/10.1093/hmg/ddu022

DOI: 10.1093/hmg/ddu022

PubMed id: 24452335

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