Age at onset in Huntington’s disease is modified by the autophagy pathway: implication of the V471A polymorphism in Atg7
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Huntington’s disease (HD) is caused by an expansion of a polyglutamine repeat of more than 35 units in the huntingtin protein. The expanded repeat length is inversely correlated with the age at onset (AAO); however, additional genetic factors apart from the expanded CAG repeat length can modify the course and the AAO in HD. Aberrations in macroautophagy have been observed in Huntington, Alzheimer, Parkinson, motor neuron and prion diseases. Therefore, we hypothesized that polymorphisms in autophagy-related (Atg) genes might contribute to the variation in the AAO. We initially tested eight single nucleotide polymorphisms in five Atg genes (Atg3, Atg5, Atg7, Atg16L1 and Beclin-1) for their frequency of ≥1%. Subsequently, we investigated the polymorphisms Atg7 V471A and Atg16L1 T281A for a disease-modifying effect in more than 900 European HD patients (including 2 populations consisting of 346 German patients and 327 patients of Italian descent). One polymorphism in the Atg7 gene that substitutes alanine for valine (V471A) showed a significant effect on the AAO (P = 0.0050) and was associated with an earlier disease onset of 4 years. Our results further support the important pathophysiological role of autophagy in HD.
KeywordsGenetic Modifier 471A Allele Mutant Huntingtin V471A Polymorphism Atg16L1 Gene
We are grateful to the patients for participating in the study, and in particular to the following neurologists and geneticists for providing DNA samples of HD patients: F. Laccone (Department of Medical Genetics, Vienna, Austria), S. Didonato and C. Gellera (National Institute of Neurology Carlo Besta, Milano, Italy), H. W. Lange (Rehazentrum, Düsseldorf, Germany), H. Weirich-Schwaiger (Medical University of Innsbruck, Innsbruck, Austria), B. Melegh (University of Pécs, Pécs, Hungary), J. T. Epplen (University of Bochum, Germany), J. Zaremba (Institute of Psychiatry and Neurology, Warsaw, Poland), A. N. Basak (Bogazici University Bebek Istanbul, Istanbul, Turkey), J. Zidovska (University and Teaching Hospital, Prague, Czech Rebublic), M. Pandolfo (Erasme Hospital, Brussels, Belgium), L. Kadasi (Slovak Academy of Sciences, Bratislava, Slovakia), M. Kvasnicova (Department of Clinical Genetics, Banska Bystrica, Slovakia), B. H. F. Weber (University of Regensburg, Regensburg, Germany), F. Kreuz (Klinikum für Psychiatrie, Chemnitz, Germany), M. Dose (BKH-Taufkirchen, Taufkirchen, Germany) and M. Stuhrmann (University of Hannover, Hannover, Germany). Special thanks to J. Tomiuk (Department of Medical Genetics, University of Tübingen, Tübingen, Germany) for statistical advice. This study was supported by the GeNeMove Network for hereditary movement disorders (01GM0603).
Conflict of interest
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