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Genetic modifiers
E04 Autophagy-related gene Atg7 is a genetic modifier of AAO specific in the Italian population
  1. C Futter1,
  2. S Metzger1,
  3. M Saukko1,
  4. L Tong2,
  5. O Riess1,
  6. HP Nguyen1,
  7. the REGISTRY Investigators of the European Huntington's Disease Network
  1. 1Department of Medical Genetics, University of Tuebingen, Tuebingen, Germany
  2. 2Department of Biological Sciences, Columbia University, New York, New York, USA


Background The only known cause of Huntington's 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 (AAO) of the disease. However, additional genetic factors apart from the expanded CAG repeat length can modify the course and the AAO in HD. Since autophagy, the major way for the degradation of mutant huntingtin, is thought to exert influence on the pathogenesis of HD, we hypothesised that autophagy-related (Atg) genes might contribute to the variation in the AAO.

Aim/method In this regard, we analysed the association of the V471A polymorphism in the autophagy-related gene Atg7 gene in two large cohorts (1st study group: 952 patients; 2nd study group (EHDN REGISTRY): 1464 patients), composed of HD patients descending from different European countries.

Results Although a polymorphism in the Atg7 gene that substitutes alanine for valine (V471A) showed a significant effect on the AAO in the first patient cohort mainly consisting of Italian and German HD patients, the significant effect of the Atg7 V471A polymorphism could not be confirmed in the second study group that was composed of European patients other than Italian and German patients. A more detailed analysis revealed a significant effect of the Atg7 V471A polymorphism on the AAO especially in the Italian population (327 patients) and was associated with a 4 years earlier disease onset.

Conclusion Therefore, we identified a genetic modifier for HD in relationship to the autophagic pathway, but with a specific effect in a single population. This result affirms the influence of genetic modifiers on the course of HD, but also suggests population-specific modifying mechanisms in the HD pathogenesis.

  • Huntington's disease
  • autophagy
  • Atg7
  • genetic modifier

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