Point Mutations at -Synuclein Gene are not Found in Korean Familial Parkinson s Disease

Transcription

1 Point Mutations at -Synuclein Gene are not Found in Korean Familial Parkinson s Disease Chul Hyoung Lyoo, M.D., Hyun Sook Kim, M.D., Yong Duk Kim, M.D., Jin Ho Kim, M.D.*, Myung Sik Lee, M.D. Department of Neurology, College of Medicine Yonsei University, Yongdong Severance Hospital, Seoul, Korea Department of Neurology, College of Medicine Chosun University, Kwangju, Korea* Background : Recent developments of molecular biological techniques have enabled the identification of genetic abnormalities responsible for the development of familial Parkinson s disease (PD). The -synuclein, a major component of Lewy body in Parkinson s disease and of non- -amyloid components of amyloid plaques in Alzheimer s disease, has been identified as one of the factors associated with neurodegenerative diseases. Ala53Thr (G209A) mutation in -synuclein was found in one Italian-American (Contursi) and five unrelated Greek familial PD with autosomal dominant inheritance. Efforts to find the same mutation in many other familial and sporadic PD patients were negative. However, another mutation (Ala30Pro(G88C)) of -synuclein was found in one German person kindred. Methods : We performed a genetic analysis to search for these two mutations in four unrelated Korean families with PD and 44 sporadic PD and 30 sporadic multisystem atrophy(msa) patients. Results : We did not find any mutations in the index patients of four families or in sporadic PD and MSA patients. Conclusions : These findings suggest the possibility that the two identified point mutations do not cause Korean sporadic and familial PD or sporadic MSA. Further evaluation including whole exons associated with the -synuclein gene is needed. J Kor Neurol Ass 17(4):534~540, 1999 Key Words : -synuclein, Parkinson s Disease, Mutation Myung Sik Lee, M.D. 534 Copyright 1999 by the Korean Neurological Association

2 Table 1. Summary of characteristics of Korean patients with familial Parkinson s disease. family patient age age at response to symptoms and signs onset levodopa A II-1 56 d 50 - bradykinesia, dysarthria, microphonia III-1 44 d 42 good bradykinesia, gait disturbance *III-3 41 d 38 good bradykinesia, rigidity, festinating gait, eye movement abnormality, peak dose dyskinesia 1.5yrs after levodopa treatment I-2 94 d seventies - unilateral rest tremor, festinating gait at late eighties B II-1 89 d mid sixties - rest tremor, postural tremor, festinating gait at late eighties *III-7 53 d 52 moderate unilateral rest tremor, bradykinesia, rigidity, C *I-2 81 d late fifties good rest tremor, bradykinesia, rigidity, severe gait disturbance, festinating gait II-3 60 d 46 good rest tremor, severe gait disturbance, rapid progression I-1 80 d - - postural tremor III-1 80 d 60 - unilateral rest tremor D III-3 73 d 67 - unilateral rest tremor *III-5 67 d 60 moderate gait disturbance, memory impairment, acalculia, dystonia d age at death suspicious individual * genetic study performed - data not available J Kor Neurol Ass / Volume 17 / July,

3 Figure 1A. Pedigree of family A Figure 1B. Pedigree of family B 536 J Kor Neurol Ass / Volume 17 / July, 1999

4 Figure 1C. Pedigree of family C Figure 1D. Pedigree of family D J Kor Neurol Ass / Volume 17 / July,

5 Figure 2. Gene study of four patients with familial Parkinson s disease.(lane 1) 100bp DNA marker(gibco BRL),(Lane 2-5) 216bp sized exon 4 amplimer undigested by Tsp45I,(Lane 6) control 151 & 136bp sized RFLP marker band. Original 287bp sized amplimer contains one Tsp45I restriction site.(lane 7-10) 395bp sized exon 3 amplimer undi - gested by Bst2UI,(Lane 11) control 117 & 100bp sized RFLP marker band. Original 217bp sized amplimer contains one Bst2UI restriction site. The letters A, B, C and D denote the family names. 538 J Kor Neurol Ass / Volume 17 / July, 1999

6 01. Duvoisin RC, Eldridge R, Williams A, Nutt J, Calne D. Twin study of Parkinson disease. N e u r o l o g y ; 3 1 ( 1 ) : Ward CD, Duvoisin RC, Ince SE, Nutt JD, Eldridge R, Calne DB. Parkinson s disease in 65 pairs of twins and in a set of quadruplets. Neurology 1983;33(7): Marder K, Tang MX, Mejia H, et al. Risk of Parkinson s disease among first-degree relatives: A community-based study. Neurology 1996;47(1): Bonifati V, Fabrizio E, Vanacore N, De Mari M, Meco G. Familial Parkinson s disease: a clinical genetic analysis. Can J Neurol Sci 1995;22(4): Plante-Bordeneuve V, Taussig D, Thomas F, Ziegler M, Said G. A clinical and genetic study of familial cases of Parkinson s disease. J Neurol Sci 1995;133(1-2): Payami H, Larsen K, Bernard S, Nutt J. Increased risk of Parkinson s disease in parents and siblings of patients. A n n N e u r o l ; 3 6 ( 4 ) : Lazzarini AM, Myers RH, Zimmerman TR, et al. A clinical genetic study of Parkinson s disease: evidence for dom- inant transmission. N e u r o l o g y 1994;44(3 Pt 1): De Michele G, Filla A, Marconi R, et al. A genetic study of Parkinson s disease. J Neural Transm Suppl 1995 ; 45 : De Michele G, Filla A, Volpe G, et al. Environmental and genetic risk factors in Parkinson s disease: a case-control study in southern Italy. Mov Disord 1996;11(1): Barbeau A, Cloutier T, Roy M, Plasse L, Paris S, Poirier 14. Kurth JH, Kurth MC, Poduslo SE, Schwankhaus JD. Asso- ciation of a monoamine oxidase B allele with Parkinson s disease. Ann Neurol 1993 ; 33 ( 4 ): Golbe LI. Alpha-synuclein and Parkinson s disease. Mov J. Ecogenetics of Parkinson s disease: 4-hydroxylation of debrisoquine. Lancet 1985;2(8466): Armstrong M, Daly AK, Cholerton S, Bateman DN, Idle JR. Mutant debrisoquine hydroxylation genes in Parkinson s disease. L a n c e t 1992 ; 339 ( 8800 ): Kurth MC, Kurth JH. Variant cytochrome P450 CYP2D6 allelic frequencies in Parkinson s disease. Am J Med Genet 1993 ; 48 ( 3 ): Hotamisligil GS, Girmen AS, Fink JS, et al. Hereditary variations in monoamine oxidase as a risk factor for Parkinson s disease. Mov Disord 1994;9(3): Disord 1999;14(1): Polymeropoulos MH. Autosomal dominant Parkinson s disease and alpha-synuclein. Ann Neurol 1998;44(3 Suppl 1):S Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson s disease. Science 1997;276(5321): Polymeropoulos MH, Higgins JJ, et al. Mapping of a gene for Parkinson s disease to chromosome 4q21-q23. Science 1996;274(5290): Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. N a t u r e ; ( ) : Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. alpha-synuclein in filamentous inclusions of Lewy bodies from Parkinson s disease and dementia with lewy bodies. Proc Natl Acad Sci USA ; 9 5 ( 1 1 ) : Munoz E, Oliva R, Obach V, et al. Identification of Spanish familial Parkinson s disease and screening for the Ala53Thr mutation of the alpha-synuclein gene in early onset patients. Neurosci Lett ; ( 1-2 ) : Vaughan JR, Farrer MJ, Wszolek ZK, et al. Sequencing of the alpha-synuclein gene in a large series of cases of familial Parkinson s disease fails to reveal any further mutations. The European Consortium on Genetic Susceptibility in Parkinson s Disease(GSPD). Hum Mol Gen ; 7 ( 4 ) : Farrer M, Wavrant-De Vrieze F, Crook R, et al. Low frequency of alpha-synuclein mutations in familial Parkinson s disease. Ann Neurol 1998;43(3): Chan P, Tanner CM, Jiang X, Langston JW. Failure to find the alpha-synuclein gene missense mutation(g209a) in 100 patients with younger onset Parkinson s disease. N e u r o l o g y J Kor Neurol Ass / Volume 17 / July,

7 ; 5 0 ( 2 ) : Kruger R, Kuhn W, Muller T, et al. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson s disease. Nat Genet 1998;18(2): Gibb WR, Lees AJ. The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson s disease. J Neurol Neurosurg Psychiatry ; 5 1 ( 6 ) : Wenning GK, Ben Shlomo Y, Magalhaes M, Daniel SE, Quinn NP. Clinical features and natural history of multiple system atrophy. An analysis of 100 cases. B r a i n ; ( P t 4 ) : Gasser T, Muller-Myhsok B, Wszolek ZK, et al. Genetic complexity and Parkinson s disease. S c i e n c e ; (5324): Scott WK, Staijich JM, Yamaoka LH, et al. Genetic complexity and Parkinson s disease. Deane Laboratory Parkinson Disease Research Group. Science 1997;277(5324): Golbe LI, Di Iorio G, Bonavita V, Miller DC, Duvoisin RC. A large kindred with autosomal dominant Parkinson s disease. Ann Neurol ; 2 7 ( 3 ) : Golbe LI, Di Iorio G, Sanges G, et al. Clinical genetic analysis of Parkinson s disease in the Contursi kindred. Ann Neurol 1996;40(5): Gai WP, Power JH, Blumbergs PC, Blessing WW. Multiplesystem atrophy: a new alpha-synuclein disease? L a n c e t ; ( ) : Gasser T, Muller-Myhsok B, Wszolek ZK, et al. A susceptibility locus for Parkinson s disease maps to chromosome 2p13. Nat Genet 1998;18(3): Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 1998;392(6676): Hattori N, Kitada T, Matsumine H, et al. Molecular genetic analysis of a novel Parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: evidence for variable homozygous deletions in the Parkin gene in affected individuals. Ann Neurol ; 4 4 ( 6 ) : Matsumine H, Yamamura Y, Hattori N, et al. A microdeletion of D6S305 in a family of autosomal recessive juvenile parkinsonism(park2). G e n o m i c s ; 4 9 ( 1 ) : J Kor Neurol Ass / Volume 17 / July, 1999