The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients.
PLoS ONE. 2013-07-22; 8(7): e68951
DOI: 10.1371/journal.pone.0068951
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1. PLoS One. 2013 Jul 22;8(7):e68951. doi: 10.1371/journal.pone.0068951. Print 2013.
The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset
specifically in Italian Huntington disease patients.
Metzger S, Walter C, Riess O, Roos RA, Nielsen JE, Craufurd D; REGISTRY
Investigators of the European Huntington’s Disease Network, Nguyen HP.
Collaborators: Bachoud-Lévi AC, Bentivoglio AR, Biunno I, Bonelli RM, Burgunder
JM, Dunnett SB, Ferreira JJ, Handley OJ, Heiberg A, Illmann T, Landwehrmeyer G,
Levey J, Ramos-Arroyo MA, Nielsen J, Koivisto SP, Päivärinta M, Roos RA,
Sebastián AR, Tabrizi S, Vandenberghe W, Verellen-Dumoulin C, Zaremba J, Uhrová
T, Wahlström J, Barth K, Correia-Guedes L, Finisterra AM, Garde MB, Bos R, Betz
S, Callaghan J, Fullam R, Ecker D, Nielsen MG, Handley OJ, Hvalstedt C, Held C,
Koppers K, Laurà M, Horta SM, Descals AM, Díaz MF, Mestre T, Minster S, Monza D,
Mütze L, Oehmen M, Townhill J, Orth M, Padieu H, Paterski L, Peppa N, Koivisto
SP, Roedig V, Rialland A, Røren N, Šašinková P, Seliverstov Y, Cubillo PT, van
Walsem MR, Wright A, Silva WV, Witjes-Anné MN, Yudina E, Zielonka D, Zielonka E,
Zinzi P, Bonelli RM, Herranhof B, Holl A, Kapfhammer HP, Koppitz M, Magnet M,
Otti D, Painold A, Reisinger K, Scheibl M, Hecht K, Lilek S, Müller N, Schöggl H,
Ullah J, Ribaï P, Verellen-Dumoulin C, Boogaerts A, Vandenberghe W, van Reijen D,
Klempíř J, Majerová V, Roth J, Nielsen J, Hjermind L, Jacobsen O, Vinthev-Jensen
T, Larsen IU, Stockholm J, Hiivola H, Martikainen K, Tuuha K, Ignatius J, Kärppä
M, Åman J, Mustonen A, Kajula O, Santala M, Allain P, Guérid MA, Gohier B,
Olivier A, Prundean A, Scherer-Gagou C, Verny C, Bost M, Babiloni B, Debruxelles
S, Duché C, Goizet C, Lafoucrière D, Jameau L, Spampinato U, De Bruycker C,
Cabaret M, Carette AS, Defebvre L, Decorte E, Delval A, Delliaux M, Destee A,
Dujardin K, Peter M, Plomhouse L, Sablonnière B, Simonin C, Defebvre L, Lemaire
MH, Manouvrier S, Thibault-Tanchou S, Vuillaume I, Krystkowiak P, Duru C, Roussel
M, Wannepain S, Berrissoul H, Bellonet M, Courtin F, Mantaux B, Fasquel V,
Godefroy O, Azulay JP, Fluchère F, Delfini M, Eusebio A, Mundler L, Longato N,
Rudolf G, Steinmetz G, Tranchant C, Wagner C, Zimmermann MA, Marcel C, Andrich J,
Ellrichmann G, Hoffmann R, Kaminski B, Saft C, Stamm C, Boelmans K, Ganos C,
Goerendt I, Hidding U, Lewerenz J, Münchau A, Orth M, Schmalfeld J, Stubbe L,
Zittel S, Bürk K, Möller JC, Rissling I, Cormio C, Sciruicchio V, Serpino C, de
Tommaso M, Capellari S, Cortelli P, Gallassi R, Poda R, Rizzo G, Scaglione C,
Abbruzzese G, di Poggio MB, Di Maria E, Ferrandes G, Mandich P, Marchese R,
Albanese A, Di Bella D, Di Donato S, Gellera C, Genitrini S, Mariotti C, Monza D,
Nanetti L, Paridi D, Soliveri P, Tomasello C, Squitieri F, Elifani F, Maglione V,
Di Pardo A, Alberti S, Griguoli A, Amico E, Martino T, Petrollini M, Bentivoglio
AR, Catalli C, Di Giacopo R, Fasano A, Frontali M, Guidubaldi A, Ialongo T,
Jacopini G, Loria G, Piano C, Chiara P, Quaranta D, Romano S, Soleti F, Spadaro
M, Zinzi P, van Hout MS, van Vugt JP, de Weert A, Bolwijn JJ, Dekker M, Leenders
KL, Bos R, Dumas EM, van den Bogaard SJ, Roos RA, ‘t Hart EP, van Duijn E, Kremer
B, Verstappen CC, Blinkenberg EØ, Hauge E, Tyvoll H, Heiberg A, van Walsem MR,
Frich J, Aaserud O, Wehus R, Bjørgo K, Fannemel M, Gørvell P, Lorentzen E,
Koivisto SP, Retterstøl L, Overland T, Stokke B, Bjørnevoll I, Sando SB,
Dziadkiewicz A, Nowak M, Robowski P, Sitek E, Slawek J, Soltan W, Szinwelski M,
Blaszcyk M, Boczarska-Jedynak M, Ciach-Wysocka E, Gorzkowska A, Jasinska-Myga B,
Opala G, Kłodowska-Duda G, Stompel D, Banaszkiewicz K, Boćwińska D, Szczudlik A,
Rudzinska M, Wójcik M, Dec M, Krawczyk M, Bojakowska-Jaremek K, Szczygieł E,
Stenwak A, Wasielewska A, Bryl A, Ciesielska A, Klimberg A, Marcinkowski J,
Sempołowicz J, Zielonka D, Samara H, Wiśniewski B, Janik P, Gogol A, Kwiecinski
H, Jamrozik Z, Kaminska A, Antczak J, Jachinska K, Rakowicz M, Richter P, Rola R,
Ryglewicz D, Sienkiewicz-Jarosz H, Stępniak I, Witkowski G, Zdzienicka E, Zaremba
J, Sułek A, Krysa W, Stepniak I, Zieora-Jakutowicz K, Júlio F, Januário C, Mestre
T, Correia-Guedes L, Coelho M, Mendes T, Valadas A, Ferreira JJ, Andrade C, Gago
M, Garrett C, Guerra MR, Lima J, Massano J, Meireles J, Herrera CD, Garcia PM,
Barrero F, Morales B, Cubo E, Mariscal N, Sánchez J, Alonso-Frech F, Perez MR,
Fenollar M, García RG, Pin Quiroga P, Vázquez Rivera S, Villanueva C, Alegre J,
Bascuñana M, Caldentey JG, Ventura MF, Ribas GG, de Yébenes JG, Moreno JL,
Cubillo PT, Ruíz PJ, Martínez-Descals A, Artiga MJ, Sánchez V, Guerrero R,
Bárcenas AH, Díaz MF, Perea MF, Fortuna L, Torres MM, Reinante G, Moreau LV,
Barbera MA, Guia DB, Hernanz LC, Catena JL, Sebastián AR, Ferrer PQ, Carruesco
GT, Bas J, Busquets N, Calopa M, Elorza MD, López CD, Durán-Sindreu Terol S,
Robert MF, Ruíz BG, Casado AG, Martínez IH, Viladrich CM, Cárdenas RP, Roca E,
Llesoy JR, Idiago JM, Vergara MR, García SS, Riballo AV, González SG, Guisasola
LM, Salvador C, Martín ES, González M, Gorospe A, Legarda I, Arques PN, Rodríguez
MJ, Vives B, Gaston I, Ramos-Arroyo MA, Martinez-Jaurrieta MD, Moreno JM, Peña
JC, Avarvarei LD, Bastida AM, Recio MF, Vergé LR, Sánchez VS, Carrillo F, Cáceres
MT, Mir P, Suarez MJ, Loutfi G, Olofsson C, Stattin EL, Westman L, Wikström B,
Pålhagen SE, Paucar M, Svenningsson P, Reza-Soltani TW, Höglund A, Sandström B,
Wahlström J, Høsterey-Ugander U, Fredlund G, Constantinescu R,
Neleborn-Lingefjärd L, Burgunder JM, Stebler Y, Kaelin A, Romero I, Schüpbach M,
Zaugg SW, Miedzybrodzka Z, Rae D, Downie L, Simpson S, Summers F, Ure A, Jack R,
Matheson K, Akhtar S, Crooks J, Curtis A, de Souza J, Rickards H, Wright J,
Barker RA, O’ Keefe D, Di Pietro A, Fisher K, Goodman A, Hill S, Mason S, Swain
R, Guzman NV, Bisson J, Busse M, Butcher C, Callaghan J, Clenaghan C, Dunnett S,
Fullam R, Handley O, Hunt S, Hughes A, Johnstone C, Jones L, Jones U, Khalil H,
Minster S, Owen M, Price K, Rose LE, Townhill J, Rosser A, Porteous M, Edwards M,
Ho C, McGill M, Pearson P, Brockie P, Foster J, Johns N, McKenzie S, Rothery J,
Thomas G, Yates S, Burrows L, Fletcher A, Harding A, Laver F, Silva M, Thomson A,
Rowett L, Gallantrae D, Longthorpe M, Markova I, Raman A, Hamer S, Yarduiman P,
Chu C, Kraus A, Wild S, Musgrave H, Rowett L, Toscano J, Jamieson S, Hobson E,
Clayton C, Dipple H, Middleton J, Freire-Patino D, Andrews T, Dougherty A,
Kavalier F, Golding C, Laing H, Lashwood A, Robertson D, Ruddy D, Whaite A,
Santhouse A, Patton M, Peterson M, Rose S, Andrews T, Bruno S, Chu E, Doherty K,
Golding C, Haider S, Hensman D, Lahiri N, Lewis M, Novak M, Patel A, Robertson N,
Rosser E, Tabrizi S, Taylor R, Warner T, Wild E, Craufurd D, Fullam R, Howard L,
Sollom A, Snowden J, Thompson J, Callaghan J, Jones M, Murphy H, Trender-Gerhard
I, Rogers D, Bek J, Oughton E, Johnson L, Hare M, Arran N, Verstraelen N,
Partington-Jones L, Huson S, Stopford C, Westmoreland L, Davidson J, Morgan K,
Savage L, Singh B, Komati S, Nemeth AH, Armstrong R, Valentine R, Siuda G,
Harrison D, Hughes M, Parkinson A, Soltysiak B, Bandmann O, Bradbury A, Gill P,
Fairtlough H, Fillingham K, Foustanos I, Kazoka M, O’ Donovan K, Peppa N, Taylor
C, Tidswell K, Quarrell O.
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.
DOI: 10.1371/journal.pone.0068951
PMCID: PMC3718802
PMID: 23894380 [Indexed for MEDLINE]