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.
Highlights
Huntington disease (HD) is one of the most common monogenetic neurodegenerative disorders and is clinically characterized by progressive development of motor disturbances as well as cognitive and psychiatric dysfunctions mainly starting at middle age [1]
HD Patients As the aim of this study is the analysis of the identified modifier polymorphism autophagyrelated gene 7 (ATG7) V471A in a second HD patients cohort, we examined a patients group consisting of 1,464 unrelated European HD patients, which were obtained by the European Huntington’s Disease Network (EHDN) ‘‘REGISTRY’’ study prior to February, 2011 (2nd European HD cohort = European Huntington Disease Network (EHDN) REGISTRY cohort)
In order to check whether the difference on the influence of the ATG7 V471A polymorphism on HD AAO in the two independent cohorts could be attributed to the origin of the patients, i.e. the different European countries, we first analysed the impact of the patients’ origin on their AAO
Summary
Huntington disease (HD) is one of the most common monogenetic neurodegenerative disorders and is clinically characterized by progressive development of motor disturbances as well as cognitive and psychiatric dysfunctions mainly starting at middle age [1]. The underlying genetic defect of HD is the expansion of an unstable CAG repeat in the HTT gene resulting in an elongated polyglutamine tract of the huntingtin protein (htt), which is inversely correlated with the age-at-onset (AAO) and the course of the disease [2,3,4]. The remaining variance of AAO may be due to modifier genes and seems to be strongly heritable. Several studies identified genetic modifiers of AAO in HD participating in glutamatergic transmission (GRIK2, GRIN2A, GRIN2B) [8,9,10,11], axonal trafficking (HAP1) [12], gene transcription (TCERG1, TP53) [13,14], energy metabolism (PPARGC1A) [15,16,17] or protein degradation (UCHL1, ATG7) [18,19,20] representing various intracellular pathways involved in pathogenic processes of HD [21]
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