OBJECTIVE: The aim of the study is to determine the frequency of parkin allelic variants in Czech early-onset Parkinson's disease patients and healthy controls. METHODS: A total of 70 early-onset Parkinson's disease patients (age at onset ≤40 years) and 75 controls were screened for the sequence variants and exon rearrangements in the parkin gene. RESULTS: Parkin mutations were identified in five patients (7.1%): the p.R334C point mutation was present in one patient, four patients had exon deletions. The detected mutations were observed in the heterozygous state except one homozygous deletion of the exon 4. No mutations were obtained in control subjects. A novel sequence variant p.V380I (c.1138G>A) was identified in one control. Non-pathogenic polymorphisms p.S167N and p.D394N were seen in similar percentage in patients and controls, polymorphism p.V380L was almost twice as frequent in controls as in patients. CONCLUSIONS: Our study contributes to the growing body of evidence on the low frequency of the parkin mutations in the early-onset Parkinson's disease suggesting the potential role of other genes in the pathogenesis of the disease.

Department of Neurology and Centre of Clinical Neuroscience 1st Faculty of Medicine and General University Hospital Charles University Prague Czech Republic

Department of Neurology and Centre of Clinical Neuroscience 1st Faculty of Medicine and General University Hospital Charles University Prague Czech Republic; Institute of Neuropsychiatric Care Prague Czech Republic

Department of Pathology and Molecular Medicine Thomayer's University Hospital Prague Czech Republic

Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine and General University Hospital Charles University Prague Czech Republic

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Jankovic J (2008) Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79: 368–376. PubMed

de Lau LM, Breteler MM (2006) Epidemiology of Parkinson's disease. Lancet Neurol 5: 525–535. PubMed

Twelves D, Perkins KS, Counsell C (2003) Systematic review of incidence studies of Parkinson's disease. Mov Disord 18: 19–31. PubMed

Schrag A, Schott JM (2006) Epidemiological, clinical, and genetic characteristics of early-onset parkinsonism. Lancet Neurol 5: 355–363. PubMed

Van Den Eeden SK, Tanner CM, Bernstein AL, Fross RD, Leimpeter A, et al. (2003) Incidence of Parkinson's disease: variation by age, gender, and race/ethnicity. Am J Epidemiol 157: 1015–1022. PubMed

Thenganatt MA, Jankovic J (2014) Parkinson disease subtypes. JAMA Neurol 71: 499–504. PubMed

Lucking CB, Durr A, Bonifati V, Vaughan J, De Michele G, et al. (2000) Association between Early-Onset Parkinson's Disease and Mutations in the Parkin Gene. N Engl J Med 342: 1560–1567. PubMed

Bruggemann N, Klein C (1993) Parkin Type of Early-Onset Parkinson Disease.

Lubbe S, Morris HR (2014) Recent advances in Parkinson's disease genetics. J Neurol 261: 259–266. PubMed

Grunewald A, Kasten M, Ziegler A, Klein C (2013) Next-generation phenotyping using the parkin example: time to catch up with genetics. JAMA Neurol 70: 1186–1191. PubMed

Marder KS, Tang MX, Mejia-Santana H, Rosado L, Louis ED, et al. (2010) Predictors of parkin mutations in early-onset Parkinson disease: the consortium on risk for early-onset Parkinson disease study. Arch Neurol 67: 731–738. PubMed PMC

Brooks J, Ding J, Simon-Sanchez J, Paisan-Ruiz C, Singleton AB, et al. (2009) Parkin and PINK1 mutations in early-onset Parkinson's disease: comprehensive screening in publicly available cases and control. J Med Genet 46: 375–381. PubMed PMC

Kilarski LL, Pearson JP, Newsway V, Majounie E, Knipe MD, et al. (2012) Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson's disease. Mov Disord 27: 1522–1529. PubMed

Koziorowski D, Hoffman-Zacharska D, Slawek J, Szirkowiec W, Janik P, et al. (2010) Low frequency of the PARK2 gene mutations in Polish patients with the early-onset form of Parkinson disease. Parkinsonism Relat Disord 16: 136–138. PubMed

Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55: 181–184. PubMed PMC

Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, et al. (1998) Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392: 605–608. PubMed

Khan NL, Graham E, Critchley P, Schrag AE, Wood NW, et al. (2003) Parkin disease: a phenotypic study of a large case series. Brain 126: 1279–1292. PubMed

Spica V, Pekmezovic T, Svetel M, Kostic VS (2013) Prevalence of non-motor symptoms in young-onset versus late-onset Parkinson's disease. J Neurol 260: 131–137. PubMed

Gallagher DA, Lees AJ, Schrag A (2010) What are the most important nonmotor symptoms in patients with Parkinson's disease and are we missing them? Mov Disord 25: 2493–2500. PubMed

Zhang Y, Wang ZZ, Sun HM (2012) Meta-analysis of the influence of Parkin p.Asp394Asn variant on the susceptibility of Parkinson's disease. Neurosci Lett 524: 60–64. PubMed

Zhang Y, Wang ZZ, Sun HM (2012) Lack of association between p.Ser167Asn variant of Parkin and Parkinson's disease: a meta-analysis of 15 studies involving 2,280 cases and 2,459 controls. Am J Med Genet B Neuropsychiatr Genet 159B: 38–47. PubMed

Zhang Y, Wang ZZ, Sun HM (2013) A meta-analysis of the relationship of the Parkin p.Val380Leu polymorphism to Parkinson's disease. Am J Med Genet B Neuropsychiatr Genet 162B: 235–244. PubMed

Kay DM, Moran D, Moses L, Poorkaj P, Zabetian CP, et al. (2007) Heterozygous parkin point mutations are as common in control subjects as in Parkinson's patients. Ann Neurol 61: 47–54. PubMed

Cookson MR, Lockhart PJ, McLendon C, O'Farrell C, Schlossmacher M, et al. (2003) RING finger 1 mutations in Parkin produce altered localization of the protein. Hum Mol Genet 12: 2957–2965. PubMed

Schlitter AM, Kurz M, Larsen JP, Woitalla D, Muller T, et al. (2006) Parkin gene variations in late-onset Parkinson's disease: comparison between Norwegian and German cohorts. Acta Neurol Scand 113: 9–13. PubMed

Corti O, Lesage S, Brice A (2011) What genetics tells us about the causes and mechanisms of Parkinson's disease. Physiol Rev 91: 1161–1218. PubMed

Chaugule VK, Burchell L, Barber KR, Sidhu A, Leslie SJ, et al. (2011) Autoregulation of Parkin activity through its ubiquitin-like domain. EMBO J 30: 2853–2867. PubMed PMC

Klein C, Lohmann-Hedrich K, Rogaeva E, Schlossmacher MG, Lang AE (2007) Deciphering the role of heterozygous mutations in genes associated with parkinsonism. Lancet Neurol 6: 652–662. PubMed

Hilker R, Klein C, Ghaemi M, Kis B, Strotmann T, et al. (2001) Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial parkinsonism associated with mutations in the parkin gene. Ann Neurol 49: 367–376. PubMed

Khan NL, Brooks DJ, Pavese N, Sweeney MG, Wood NW, et al. (2002) Progression of nigrostriatal dysfunction in a parkin kindred: an [18F]dopa PET and clinical study. Brain 125: 2248–2256. PubMed

Hagenah JM, Konig IR, Becker B, Hilker R, Kasten M, et al. (2007) Substantia nigra hyperechogenicity correlates with clinical status and number of Parkin mutated alleles. J Neurol 254: 1407–1413. PubMed

Walter U, Klein C, Hilker R, Benecke R, Pramstaller PP, et al. (2004) Brain parenchyma sonography detects preclinical parkinsonism. Mov Disord 19: 1445–1449. PubMed

Guerrero Camacho JL, Monroy Jaramillo N, Yescas Gomez P, Rodriguez Violante M, Boll Woehrlen C, et al. (2012) High frequency of Parkin exon rearrangements in Mexican-mestizo patients with early-onset Parkinson's disease. Mov Disord 27: 1047–1051. PubMed

Padmaja MV, Jayaraman M, Srinivasan AV, Srisailapathy CR, Ramesh A (2012) PARK2 gene mutations in early onset Parkinson's disease patients of South India. Neurosci Lett 523: 145–147. PubMed

Monroy-Jaramillo N, Guerrero-Camacho JL, Rodriguez-Violante M, Boll-Woehrlen MC, Yescas-Gomez P, et al. (2014) Genetic mutations in early-onset Parkinson's disease Mexican patients: molecular testing implications. Am J Med Genet B Neuropsychiatr Genet 165B: 235–244. PubMed

Gaweda-Walerych K, Safranow K, Jasinska-Myga B, Bialecka M, Klodowska-Duda G, et al. (2012) PARK2 variability in Polish Parkinson's disease patients–interaction with mitochondrial haplogroups. Parkinsonism Relat Disord 18: 520–524. PubMed PMC

Moura KC, Campos Junior M, de Rosso AL, Nicaretta DH, Pereira JS, et al. (2013) Genetic analysis of PARK2 and PINK1 genes in Brazilian patients with early-onset Parkinson's disease. Dis Markers 35: 181–185. PubMed PMC

Bozi M, Papadimitriou D, Antonellou R, Moraitou M, Maniati M, et al. (2013) Genetic assessment of familial and early-onset Parkinson's disease in a Greek population. Eur J Neurol. PubMed

de Mena L, Samaranch LL, Coto E, Cardo LF, Ribacoba R, et al. (2013) Mutational screening of PARKIN identified a 3' UTR variant (rs62637702) associated with Parkinson's disease. J Mol Neurosci 50: 264–269. PubMed

Fiala O, Pospisilova L, Prochazkova J, Matejckova M, Martasek P, et al. (2010) Parkin mutations and phenotypic features in Czech patients with early-onset Parkinson's disease. Neuro Endocrinol Lett 31: 187–192. PubMed

Choi JM, Woo MS, Ma HI, Kang SY, Sung YH, et al. (2008) Analysis of PARK genes in a Korean cohort of early-onset Parkinson disease. Neurogenetics 9: 263–269. PubMed

Mellick GD, Siebert GA, Funayama M, Buchanan DD, Li Y, et al. (2009) Screening PARK genes for mutations in early-onset Parkinson's disease patients from Queensland, Australia. Parkinsonism Relat Disord 15: 105–109. PubMed

New endemic familial parkinsonism in south Moravia, Czech Republic and its genetical background