title: Age at onset in Huntington's disease is modified by the autophagy pathway: implication of the V471A polymorphism in Atg7.
abstract: 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.
authors.affiliation: Department of Medical Genetics, University of Tuebingen, Calwerstr. 7, 72076, Tübingen, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Metzger
authors.forename: Meiju
authors.initials: M
authors.lastname: Saukko
authors.forename: Hong
authors.initials: H
authors.lastname: Van Che
authors.forename: Liang
authors.initials: L
authors.lastname: Tong
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Puder
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.forename: Huu Phuc
authors.initials: HP
authors.lastname: Nguyen
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D001343:Autophagy / Q000235:genetics*; D000071193:Autophagy-Related Protein 7; D002648:Child; D002675:Child, Preschool; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D006816:Huntington Disease / Q000453:epidemiology / Q000235:genetics*; D015810:Linkage Disequilibrium; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000235:genetics; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics*; D055815:Young Adult
chemical_list: C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes