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PLOS ONE  2013 

The V471A Polymorphism in Autophagy-Related Gene ATG7 Modifies Age at Onset Specifically in Italian Huntington Disease Patients

DOI: 10.1371/journal.pone.0068951

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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.

References

[1]  Bates G, Harper P, Jones L (2002) Huntington’s disease. 3. Oxford: Oxford University press.
[2]  Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann J, et al. (1993) The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington’s disease. Nat Genet 4: 398–403.
[3]  Duyao M, Ambrose C, Myers R, Noveletto A, Persichetti F, et al. (1993) Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nat Genet 4: 387–392.
[4]  The Huntington’s Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is unstable on Huntington’s disease chromosomes. Cell 26: 971–983.
[5]  Brinkman RR, Mezei MM, Theilman J, Almqvist E, Hayden MR (1997) The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size. Am J Hum Genet 60: 1202–1210.
[6]  Lucotte G, Turpin JC, Riess O, Epplen JT, Siedlaczk I, et al. (1995) Confidence intervals for predicted age of onset, given the size of (CAG)n repeat, in Huntington’s disease. Hum Genet 95: 231–232.
[7]  Trembath MK, Horton ZA, Tippett L, Hogg V, Collins VR, et al. (2010) A retrospective study of the impact of lifestyle on age at onset of Huntington disease. Mov Disord 25(10): 1444–1450 doi: 10.1002/mds.23108.
[8]  Rubinsztein DC, Leggo J, Chiano M, Dodge A, Norbury G, et al. (1997) Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease. Proc Natl Acad Sci U S A 94(8): 3872–3876.
[9]  MacDonald ME, Vonsattel JP, Shrinidhi J, Couropmitree NN, Cupples LA, et al. (1999) Evidence for the GluR6 gene associated with younger onset age of Huntington’s disease. Neurology 53(6): 1330–1332.
[10]  Arning L, Kraus PH, Valentin S, Saft C, Andrich J, et al. (2005) NR2A and NR2B receptor gene variations modify age at onset in Huntington disease. Neurogenetics 6(1): 25–28.
[11]  Saft C, Epplen JT, Wieczorek S, Landwehrmeyer GB, Roos RA, et al. (2011) NMDA receptor gene variations as modifiers in Huntington disease: a replication study. PLoS Curr 3: RRN1247 doi: 10.1371/currents.RRN1247.
[12]  Metzger S, Rong J, Nguyen HP, Cape A, Tomiuk J, et al. (2008) Huntingtin-associated protein-1 is a modifier of the age-at-onset of Huntington’s disease. Hum Mol Genet 17(8): 1137–1146 doi: 10.1093/hmg/ddn003.
[13]  Holbert S, Denghien I, Kiechle T, Rosenblatt A, Wellington C, et al. (2001) The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: neuropathologic and genetic evidence for a role in Huntington’s disease pathogenesis. Proc Natl Acad Sci U S A 98(4): 1811–1816.
[14]  Chattopadhyay B, Baksi K, Mukhopadhyay S, Bhattacharyya NP (2005) Modulation of age at onset of Huntington disease patients by variations in TP53 and human caspase activated DNase (hCAD) genes. Neurosci Lett 374(2): 81–86.
[15]  Taherzadeh-Fard E, Saft C, Andrich J, Wieczorek S, Arning L (2009) PGC-1alpha as modifier of onset age in Huntington disease. Mol Neurodegener 4: 10 doi: 10.1186/1750-1326-4-10.
[16]  Weydt P, Soyal SM, Gellera C, Didonato S, Weidinger C, et al. (2009) The gene coding for PGC-1alpha modifies age at onset in Huntington’s Disease. Mol Neurodegener 4: 3 doi: 10.1186/1750-1326-4-3.
[17]  Che HV, Metzger S, Portal E, Deyle C, Riess O, et al. (2011) Localization of sequence variations in PGC-1α influence their modifying effect in Huntington disease. Mol Neurodegener 6(1): 1 doi: 10.1186/1750-1326-6-1.
[18]  Nazé P, Vuillaume I, Destée A, Pasquier F, Sablonnière B (2002) Mutation analysis and association studies of the ubiquitin carboxy-terminal hydrolase L1 gene in Huntington’s disease. Neurosci Lett 328(1): 1–4.
[19]  Metzger S, Bauer P, Tomiuk J, Laccone F, Didonato S, et al. (2006) The S18Y polymorphism in the UCHL1 gene is a genetic modifier in Huntington’s disease. Neurogenetics 7(1): 27–30.
[20]  Metzger S, Saukko M, Van Che H, Tong L, Puder Y, et al. (2010) Age at onset in Huntington’s disease is modified by the autophagy pathway: implication of the V471A polymorphism in Atg7. Hum Genet 128(4): 453–459 doi: 10.1007/s00439-010-0873-9.
[21]  Arning L, Epplen JT (2012) Genetic modifiers of Huntington’s disease: beyond CAG. Future Neurol 7: 93–109.
[22]  Klionsky DJ, Ohsumi Y (1999) Vacuolar import of proteins and organelles from the cytoplasm. Annu Rev Cell Dev Biol 15: 1–32.
[23]  Ravikumar B, Duden R, Rubinsztein DC (2002) Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 11(9): 1107–1117.
[24]  Verhoef LG, Lindsten K, Masucci MG, Dantuma NP (2002) Aggregate formation inhibits proteasomal degradation of polyglutamine proteins. Hum Mol Genet 11(22): 2689–2700.
[25]  Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, et al. (2005) Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol 169(3): 425–434.
[26]  Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, et al. (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441(7095): 880–884.
[27]  Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, et al. (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36(6): 585–595.
[28]  Sarkar S, Floto RA, Berger Z, Imarisio S, Cordenier A, et al. (2005) Lithium induces autophagy by inhibiting inositol monophosphatase. J Cell Biol 170(7): 1101–1111.
[29]  Orth M, European Huntington’s Disease Network, Handley OJ, Schwenke C, Dunnett S, et al. (2011) Observing Huntington’s disease: the European Huntington’s Disease Network’s REGISTRY. J Neurol Neurosurg Psychiatry 82(12): 1409–1412 doi: 10.1136/jnnp.2010.209668.
[30]  den Dunnen JT, Antonarakis SE (2001) Nomenclature for the description of human sequence variations. Hum Genet 109(1): 121–124.
[31]  Novelletto A, Persichetti F, Sabbadini G, Mandich P, Bellone E, et al. (1994) Analysis of the trinucleotide repeat expansion in Italian families affected with Huntington disease. Hum Mol Genet 3(1): 93–98.
[32]  Stine OC, Pleasant N, Franz ML, Abbott MH, Folstein SE, et al. (1993) Correlation between the onset age of Huntington’s disease and length of the trinucleotide repeat in IT-15. Hum Mol Genet 2(10): 1547–1549.
[33]  The U.S.–Venezuela Collaborative Research Project, Wexler NS (2004) Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington’s disease age of onset. Proc Natl Acad Sci USA 9: 3498–3503.
[34]  Rosenblatt A, Brinkman RR, Liang KY, Almqvist EW, Margolis RL, et al. (2001) Familial influence on age of onset among siblings with Huntington’s disease. Am J Med Genet 105: 399–403.
[35]  Li JL, Hayden MR, Almqvist EW, Brinkman RR, Durr A, et al. (2003) A genome scan for modifiers of age at onset in Huntington disease: the HD MAPS study. Am J Hum Genet 73: 682–687.
[36]  Alberch J, López M, Badenas C, Carrasco JL, Milà M, et al. (2005) Association between BDNF Val66Met polymorphism and age at onset in Huntington disease. Neurology 65(6): 964–965.
[37]  Di Maria E, Marasco A, Tartari M, Ciotti P, Abbruzzese G, et al. (2006) No evidence of association between BDNF gene variants and age-at-onset of Huntington’s disease. Neurobiol Dis 24(2): 274–279.
[38]  Kishikawa S, Li JL, Gillis T, Hakky MM, Warby S, et al. (2006) Brain-derived neurotrophic factor does not influence age at neurologic onset of Huntington’s disease. Neurobiol Dis 24(2): 280–285.
[39]  Andresen JM, Gayán J, Cherny SS, Brocklebank D, Alkorta-Aranburu G, et al. (2007) Replication of twelve association studies for Huntington’s disease residual age of onset in large Venezuelan kindreds. J Med Genet 44(1): 44–50.
[40]  Lee JH, Lee JM, Ramos EM, Gillis T, Mysore JS, et al. (2012) TAA repeat variation in the GRIK2 gene does not influence age at onset in Huntington’s disease. Biochem Biophys Res Commun 424(3): 404–408.
[41]  Metzger S, Bauer P, Tomiuk J, Laccone F, Didonato S, et al. (2006) Genetic analysis of candidate genes modifying the age-at-onset in Huntington’s disease. Hum Genet 120(2): 285–292.
[42]  Aziz NA, van Roon-Mom WM, Roos RA (2011) CAG repeat size in the normal HTT allele and age of onset in Huntington’s disease. Mov Disord 26(13): 2450–2451 doi: 10.1002/mds.23849.
[43]  Djoussé L, Knowlton B, Hayden M, Almqvist EW, Brinkman R, et al. (2003) Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease. Am J Med Genet A 119A(3): 279–282.
[44]  Kehoe P, Krawczak M, Harper PS, Owen MJ, Jones AL (1999) Age of onset in Huntington disease: sex specific influence of apolipoprotein E genotype and normal CAG repeat length. J Med Genet 36(2): 108–111.
[45]  Klempí? J, Zidovská J, Stochl J, Ing VK, Uhrová T, et al. (2011) The number of CAG repeats within the normal allele does not influence the age of onset in Huntington’s disease. Mov Disord 26(1): 125–129 doi: 10.1002/mds.23436.
[46]  Guerini FR, Beghi E, Riboldazzi G, Zangaglia R, Pianezzola C, et al. (2009) BDNF Val66Met polymorphism is associated with cognitive impairment in Italian patients with Parkinson’s disease. Eur J Neurol 16(11): 1240–1245 doi: 10.1111/j.1468-1331.2009.02706.x.
[47]  Karakasis C, Kalinderi K, Katsarou Z, Fidani L, Bostantjopoulou S (2011) Association of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism with Parkinson’s disease in a Greek population. J Clin Neurosci 18(12): 1744–1745 doi: 10.1016/j.jocn.2011.03.015.
[48]  H?kansson A, Melke J, Westberg L, Shahabi HN, Buervenich S, et al. (2003) Lack of association between the BDNF Val66Met polymorphism and Parkinson’s disease in a Swedish population. Ann Neurol 53(6): 823.
[49]  Saarela MS, Lehtimaki T, Rinne JO, Huhtala H, Rontu R, et al. (2006) No association between the brain-derived neurotrophic factor 196 G>A or 270 C>T polymorphisms and Alzheimer’s or Parkinson’s disease. Folia Neuropathol 44(1): 12–16.
[50]  Li JL, Hayden MR, Almqvist EW, Brinkman RR, Durr A, et al. (2003) A genome scan for modifiers of age at onset in Huntington disease: The HD MAPS study. Am J Hum Genet 73(3): 682–687.
[51]  Li JL, Hayden MR, Warby SC, Durr A, Morrison PJ, et al. (2006) Genome-wide significance for a modifier of age at neurological onset in Huntington’s disease at 6q23–24: the HD MAPS study. BMC Med Genet 7: 71.
[52]  Gayán J, Brocklebank D, Andresen JM (2008) Alkorta-Aranburu G; US-Venezuela Collaborative Research Group, et al (2008) Genomewide linkage scan reveals novel loci modifying age of onset of Huntington’s disease in the Venezuelan HD kindreds. Genet Epidemiol 32(5): 445–453 doi: 10.1002/gepi.20317.
[53]  Ramos EM, Latourelle JC, Lee JH, Gillis T, Mysore JS, et al. (2012) Population stratification may bias analysis of PGC-1α as a modifier of age at Huntington disease motor onset. Hum Genet 131(12): 1833–1840 doi: 10.1007/s00439-012-1205-z.

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