Journal of the Korean Medical Association (대한의사협회지)

Korean Medical Association (대한의사협회)
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Genetics in Parkinson's disease

파킨슨병의 유전 인자

  • Chung, Sun Ju (Parkinson/Alzheimer Center, Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine)
  • 정선주 (울산대학교 의과대학 서울아산병원 신경과, 파킨슨/알츠하이머 센터)
  • Published : 2011.01.10
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Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by a large number of motor and non-motor features that can cause functional disability. Several gene mutations have been identified as causing familial PD. Most sporadic PD is caused by a complex etiology stemming from various genetic and environmental factors. Over the past 10 years, genetic research on PD has changed our conventional wisdom that PD was not a genetic disorder. Genetic findings have contributed to our understanding of the molecular etiology and pathogenesis of PD. Many mutations in a growing number of genes have been identified as causing monogenic forms of PD. Genome-wide association studies have become increasingly widely used to determine genomic regions that may contain loci influencing the risk of PD, providing new biological insights. Further studies will be performed to elucidate how complex interactions among genetics, epigenetics and the environment combine to shape phenotypes of PD. This advancement of genetics research on PD has begun to impact on clinical practice, and this impact seems to be increasing.

Keywords

References

  1. Lang AE, Lozano AM. Parkinson's disease: first of two parts. N Engl J Med 1998;339:1044-1053. https://doi.org/10.1056/NEJM199810083391506
  2. Elbaz A, Bower JH, Peterson BJ, Maraganore DM, McDonnell SK, Ahlskog JE, Schaid DJ, Rocca WA. Survival study of Parkinson disease in Olmsted County, Minnesota. Arch Neurol 2003;60:91-96. https://doi.org/10.1001/archneur.60.1.91
  3. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 1997;276: 2045-2047. https://doi.org/10.1126/science.276.5321.2045
  4. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature 1997; 388:839-840. https://doi.org/10.1038/42166
  5. Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet 1998;18:106-108. https://doi.org/10.1038/ng0298-106
  6. Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atares B, Llorens V, Gomez Tortosa E, del Ser T, Munoz DG, de Yebenes JG. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 2004;55: 164-173. https://doi.org/10.1002/ana.10795
  7. Golbe LI, Di Iorio G, Sanges G, Lazzarini AM, La Sala S, Bonavita V, Duvoisin RC. Clinical genetic analysis of Parkinson's disease in the Contursi kindred. Ann Neurol 1996; 40:767-775. https://doi.org/10.1002/ana.410400513
  8. Duda JE, Giasson BI, Mabon ME, Miller DC, Golbe LI, Lee VM, Trojanowski JQ. Concurrence of alpha-synuclein and tau brain pathology in the Contursi kindred. Acta Neuropathol 2002;104:7-11. https://doi.org/10.1007/s00401-002-0563-3
  9. Farrer MJ. Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Genet 2006;7:306-318.
  10. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998;392:605-608. https://doi.org/10.1038/33416
  11. Chung SJ, Park HK, Ki CS, Kim MJ, Lee MC. Marked diurnal fluctuation and rest benefit in a patient with parkin mutation. Mov Disord 2008;23:624-626. https://doi.org/10.1002/mds.21951
  12. Lucking CB, Durr A, Bonifati V, Vaughan J, De Michele G, Gasser T, Harhangi BS, Meco G, Denefle P, Wood NW, Agid Y, Brice A. Association between early-onset Parkinson's disease and mutations in the parkin gene. N Engl J Med 2000;342: 1560-1567. https://doi.org/10.1056/NEJM200005253422103
  13. Ishikawa A, Takahashi H. Clinical and neuropathological aspects of autosomal recessive juvenile parkinsonism. J Neurol 1998;245(11 Suppl 3):P4-P9. https://doi.org/10.1007/PL00007745
  14. Leroy E, Boyer R, Auburger G, Leube B, Ulm G, Mezey E, Harta G, Brownstein MJ, Jonnalagada S, Chernova T, Dehejia A, Lavedan C, Gasser T, Steinbach PJ, Wilkinson KD, Polymeropoulos MH. The ubiquitin pathway in Parkinson's disease. Nature 1998;395:451-452. https://doi.org/10.1038/26652
  15. Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, Gonzalez-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 2004;304:1158-1160. https://doi.org/10.1126/science.1096284
  16. Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003;299:256-259. https://doi.org/10.1126/science.1077209
  17. Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Muller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T. Mutations in LRRK2 cause autosomaldominant parkinsonism with pleomorphic pathology. Neuron 2004;44:601-607. https://doi.org/10.1016/j.neuron.2004.11.005
  18. Berg D, Schweitzer K, Leitner P, Zimprich A, Lichtner P, Belcredi P, Brussel T, Schulte C, Maass S, Nagele T. Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson's disease. Brain 2005;128(Pt 12):3000-3011. https://doi.org/10.1093/brain/awh666
  19. Lesage S, Durr A, Tazir M, Lohmann E, Leutenegger AL, Janin S, Pollak P, Brice A. LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. N Engl J Med 2006;354:422- 423. https://doi.org/10.1056/NEJMc055540
  20. Najim al-Din AS, Wriekat A, Mubaidin A, Dasouki M, Hiari M. Pallido-pyramidal degeneration, supranuclear upgaze paresis and dementia: Kufor-Rakeb syndrome. Acta Neurol Scand 1994;89:347-352.
  21. Schneider SA, Paisan-Ruiz C, Quinn NP, Lees AJ, Houlden H, Hardy J, Bhatia KP. ATP13A2 mutations (PARK9) cause neurodegeneration with brain iron accumulation. Mov Disord 2010;25:979-984. https://doi.org/10.1002/mds.22947
  22. Lautier C, Goldwurm S, Durr A, Giovannone B, Tsiaras WG, Pezzoli G, Brice A, Smith RJ. Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial Parkinson disease. Am J Hum Genet 2008;82:822-833. https://doi.org/10.1016/j.ajhg.2008.01.015
  23. Strauss KM, Martins LM, Plun-Favreau H, Marx FP, Kautzmann S, Berg D, Gasser T, Wszolek Z, Muller T, Bornemann A, Wolburg H, Downward J, Riess O, Schulz JB, Kruger R. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum Mol Genet 2005;14:2099- 2111. https://doi.org/10.1093/hmg/ddi215
  24. Morgan NV, Westaway SK, Morton JE, Gregory A, Gissen P, Sonek S, Cangul H, Coryell J, Canham N, Nardocci N, Zorzi G, Pasha S, Rodriguez D, Desguerre I, Mubaidin A, Bertini E, Trembath RC, Simonati A, Schanen C, Johnson CA, Levinson B, Woods CG, Wilmot B, Kramer P, Gitschier J, Maher ER, Hayflick SJ. PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nat Genet 2006;38:752-754. https://doi.org/10.1038/ng1826
  25. Shojaee S, Sina F, Banihosseini SS, Kazemi MH, Kalhor R, Shahidi GA, Fakhrai-Rad H, Ronaghi M, Elahi E. Genome-wide linkage analysis of a Parkinsonian-pyramidal syndrome pedigree by 500 K SNP arrays. Am J Hum Genet 2008;82:1375 - 1384. https://doi.org/10.1016/j.ajhg.2008.05.005
  26. Di Fonzo A, Dekker MC, Montagna P, Baruzzi A, Yonova EH, Correia Guedes L, Szczerbinska A, Zhao T, Dubbel-Hulsman LO, Wouters CH, de Graaff E, Oyen WJ, Simons EJ, Breedveld GJ, Oostra BA, Horstink MW, Bonifati V. FBXO7 mutations cause autosomal recessive, early-onset parkinsonianpyramidal syndrome. Neurology 2009;72:240-245. https://doi.org/10.1212/01.wnl.0000338144.10967.2b
  27. Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, Kawaguchi T, Tsunoda T, Watanabe M, Takeda A, Tomiyama H, Nakashima K, Hasegawa K, Obata F, Yoshikawa T, Kawakami H, Sakoda S, Yamamoto M, Hattori N, Murata M, Nakamura Y, Toda T. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat Genet 2009;41:1303-1307. https://doi.org/10.1038/ng.485
  28. Tan EK, Kwok HH, Tan LC, Zhao WT, Prakash KM, Au WL, Pavanni R, Ng YY, Satake W, Zhao Y, Toda T, Liu JJ. Analysis of GWAS-linked loci in Parkinson disease reaffirms PARK16 as a susceptibility locus. Neurology 2010;75:508-512. https://doi.org/10.1212/WNL.0b013e3181eccfcd
  29. Eblan MJ, Walker JM, Sidransky E. The glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N Engl J Med 2005;352:728-731. https://doi.org/10.1056/NEJM200502173520719
  30. Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, Bar-Shira A, Berg D, Bras J, Brice A, Chen CM, Clark LN, Condroyer C, De Marco EV, Durr A, Eblan MJ, Fahn S, Farrer MJ, Fung HC, Gan-Or Z, Gasser T, Gershoni-Baruch R, Giladi N, Griffith A, Gurevich T, Januario C, Kropp P, Lang AE, Lee-Chen GJ, Lesage S, Marder K, Mata IF, Mirelman A, Mitsui J, Mizuta I, Nicoletti G, Oliveira C, Ottman R, Orr- Urtreger A, Pereira LV, Quattrone A, Rogaeva E, Rolfs A, Rosenbaum H, Rozenberg R, Samii A, Samaddar T, Schulte C, Sharma M, Singleton A, Spitz M, Tan EK, Tayebi N, Toda T, Troiano AR, Tsuji S, Wittstock M, Wolfsberg TG, Wu YR, Zabetian CP, Zhao Y, Ziegler SG. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med 2009;361:1651-1661. https://doi.org/10.1056/NEJMoa0901281
  31. Makino S, Kaji R, Ando S, Tomizawa M, Yasuno K, Goto S, Matsumoto S, Tabuena MD, Maranon E, Dantes M, Lee LV, Ogasawara K, Tooyama I, Akatsu H, Nishimura M, Tamiya G. Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism. Am J Hum Genet 2007;80:393-406. https://doi.org/10.1086/512129
  32. Evidente VG, Nolte D, Niemann S, Advincula J, Mayo MC, Natividad FF, Muller U. Phenotypic and molecular analyses of X-linked dystonia-parkinsonism ("lubag") in women. Arch Neurol 2004;61:1956-1959. https://doi.org/10.1001/archneur.61.12.1956
  33. de Carvalho Aguiar P, Sweadner KJ, Penniston JT, Zaremba J, Liu L, Caton M, Linazasoro G, Borg M, Tijssen MA, Bressman SB, Dobyns WB, Brashear A, Ozelius LJ. Mutations in the Na+/K+ -ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism. Neuron 2004;43:169-175. https://doi.org/10.1016/j.neuron.2004.06.028
  34. Brashear A, Dobyns WB, de Carvalho Aguiar P, Borg M, Frijns CJ, Gollamudi S, Green A, Guimaraes J, Haake BC, Klein C, Linazasoro G, Munchau A, Raymond D, Riley D, Saunders-Pullman R, Tijssen MA, Webb D, Zaremba J, Bressman SB, Ozelius LJ. The phenotypic spectrum of rapid-onset dystonia-parkinsonism (RDP) and mutations in the ATP1A3 gene. Brain 2007;130:828-835. https://doi.org/10.1093/brain/awl340
  35. Maraganore DM, de Andrade M, Lesnick TG, Strain KJ, Farrer MJ, Rocca WA, Pant PV, Frazer KA, Cox DR, Ballinger DG. High-resolution whole-genome association study of Parkinson disease. Am J Hum Genet 2005;77:685-693. https://doi.org/10.1086/496902
  36. Fung HC, Scholz S, Matarin M, Simon-Sanchez J, Hernandez D, Britton A, Gibbs JR, Langefeld C, Stiegert ML, Schymick J, Okun MS, Mandel RJ, Fernandez HH, Foote KD, Rodriguez RL, Peckham E, De Vrieze FW, Gwinn-Hardy K, Hardy JA, Singleton A. Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol 2006;5:911-916. https://doi.org/10.1016/S1474-4422(06)70578-6
  37. Elbaz A, Nelson LM, Payami H, Ioannidis JP, Fiske BK, Annesi G, Carmine Belin A, Factor SA, Ferrarese C, Hadjigeorgiou GM, Higgins DS, Kawakami H, Kruger R, Marder KS, Mayeux RP, Mellick GD, Nutt JG, Ritz B, Samii A, Tanner CM, Van Broeckhoven C, Van Den Eeden SK, Wirdefeldt K, Zabetian CP, Dehem M, Montimurro JS, Southwick A, Myers RM, Trikalinos TA. Lack of replication of thirteen single-nucleotide polymorphisms implicated in Parkinson's disease: a largescale international study. Lancet Neurol 2006;5:917-923. https://doi.org/10.1016/S1474-4422(06)70579-8
  38. Pankratz N, Wilk JB, Latourelle JC, DeStefano AL, Halter C, Pugh EW, Doheny KF, Gusella JF, Nichols WC, Foroud T, Myers RH. Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Hum Genet 2009; 124:593-605. https://doi.org/10.1007/s00439-008-0582-9
  39. Simon-Sanchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, Paisan-Ruiz C, Lichtner P, Scholz SW, Hernandez DG, Kruger R, Federoff M, Klein C, Goate A, Perlmutter J, Bonin M, Nalls MA, Illig T, Gieger C, Houlden H, Steffens M, Okun MS, Racette BA, Cookson MR, Foote KD, Fernandez HH, Traynor BJ, Schreiber S, Arepalli S, Zonozi R, Gwinn K, van der Brug M, Lopez G, Chanock SJ, Schatzkin A, Park Y, Hollenbeck A, Gao J, Huang X, Wood NW, Lorenz D, Deuschl G, Chen H, Riess O, Hardy JA, Singleton AB, Gasser T. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet 2009;41:1308-1312. https://doi.org/10.1038/ng.487
  40. Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D, Kay DM, Doheny KF, Paschall J, Pugh E, Kusel VI, Collura R, Roberts J, Griffith A, Samii A, Scott WK, Nutt J, Factor SA, Payami H. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nat Genet 2010;42:781-785. https://doi.org/10.1038/ng.642
  41. Maraganore DM, de Andrade M, Elbaz A, Farrer MJ, Ioannidis JP, Kruger R, Rocca WA, Schneider NK, Lesnick TG, Lincoln SJ, Hulihan MM, Aasly JO, Ashizawa T, Chartier-Harlin MC, Checkoway H, Ferrarese C, Hadjigeorgiou G, Hattori N, Kawakami H, Lambert JC, Lynch T, Mellick GD, Papapetropoulos S, Parsian A, Quattrone A, Riess O, Tan EK, Van Broeckhoven C. Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 2006;296:661-670. https://doi.org/10.1001/jama.296.6.661
  42. Chung SJ, Armasu SM, Biernacka JM, Lesnick TG, Rider DN, Lincoln SJ, Ortolaza AI, Farrer MJ, Cunningham JM, Rocca WA, Maraganore DM. Common variants in PARK loci and related genes and Parkinson's disease. Mov Disord 2010 Dec 13 [Epub]. DOI: 10.1002/mds.23376.