The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

Silke Metzger, Carolin Walter, Olaf Riess, Raymund A C Roos, Jørgen E Nielsen, David Craufurd, Huu Phuc Nguyen, REGISTRY Investigators of the European Huntington’s Disease Network, Zofia Helena Miedzybrodzka

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the "REGISTRY" cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis.

Original languageEnglish
Article numbere68951
JournalPloS ONE
Volume8
Issue number7
DOIs
Publication statusPublished - 22 Jul 2013

Fingerprint

autophagy
Huntington Disease
Autophagy
Polymorphism
Age of Onset
Genes
genetic polymorphism
genes
pathogenesis
modifiers (genes)
disease course
Population

Keywords

  • Adolescent
  • Adult
  • Age of Onset
  • Aged
  • Autophagy
  • Child
  • Child, Preschool
  • Cohort Studies
  • Gene Frequency
  • Genotype
  • Humans
  • Huntington Disease
  • Italy
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Ubiquitin-Activating Enzymes
  • Young Adult

Cite this

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients. / Metzger, Silke; Walter, Carolin; Riess, Olaf; Roos, Raymund A C; Nielsen, Jørgen E; Craufurd, David; Nguyen, Huu Phuc; REGISTRY Investigators of the European Huntington’s Disease Network ; Miedzybrodzka, Zofia Helena.

In: PloS ONE, Vol. 8, No. 7, e68951, 22.07.2013.

Research output: Contribution to journalArticle

Metzger, S, Walter, C, Riess, O, Roos, RAC, Nielsen, JE, Craufurd, D, Nguyen, HP, REGISTRY Investigators of the European Huntington’s Disease Network & Miedzybrodzka, ZH 2013, 'The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients', PloS ONE, vol. 8, no. 7, e68951. https://doi.org/10.1371/journal.pone.0068951
Metzger, Silke ; Walter, Carolin ; Riess, Olaf ; Roos, Raymund A C ; Nielsen, Jørgen E ; Craufurd, David ; Nguyen, Huu Phuc ; REGISTRY Investigators of the European Huntington’s Disease Network ; Miedzybrodzka, Zofia Helena. / The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients. In: PloS ONE. 2013 ; Vol. 8, No. 7.
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AU - Nielsen, Jørgen E

AU - Craufurd, David

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