J Clin Neurol.  2014 Jul;10(3):244-248. 10.3988/jcn.2014.10.3.244.

Analysis of Dosage Mutation in PARK2 among Korean Patients with Early-Onset or Familial Parkinson's Disease

• Chu MK
• Kim WC
• Choi JM
• Hong JH
• Kang SY
• Ma HI
• Kim YJ

• KMID: 2179452
• DOI: http://doi.org/10.3988/jcn.2014.10.3.244

Abstract

BACKGROUND AND PURPOSE
There is some controversy regarding heterozygous mutations of the gene encoding parkin (PARK2) as risk factors for Parkinson's disease (PD), and all previous studies have been performed in non-Asian populations. Dosage mutation of PARK2, rather than a point mutation or small insertion/deletion mutation, was reported to be a risk factor for familial PD; dosage mutation of PARK2 is common in Asian populations.
METHODS
We performed a gene-dosage analysis of PARK2 using real-time polymerase chain reaction for 189 patients with early-onset PD or familial PD, and 191 control individuals. In the case of PD patients with heterozygous gene-dosage mutation, we performed a sequencing analysis to exclude compound heterozygous mutations. The association between heterozygous mutation of PARK2 and PD was tested.
RESULTS
We identified 22 PD patients with PARK2 mutations (11.6%). Five patients (2.6%) had compound heterozygous mutations, and 13 patients (6.9%) had a heterozygous mutation. The phase could not be determined in one patient. Three small sequence variations were found in 30 mutated alleles (10.0%). Gene-dosage mutation accounted for 90% of all of the mutations found. The frequency of a heterozygous PARK2 gene-dosage mutation was higher in PD patients than in the controls.
CONCLUSIONS
Heterozygous gene-dosage mutation of PARK2 is a genetic risk factor for patients with early-onset or familial PD in Koreans.

Keyword

Parkinson's disease; PARK2; gene-dosage change; risk factor

MeSH Terms

Alleles
Asian Continental Ancestry Group
Humans
Parkinson Disease*
Point Mutation
Real-Time Polymerase Chain Reaction
Risk Factors

Reference

1. Singleton AB, Farrer MJ, Bonifati V. The genetics of Parkinson's disease: progress and therapeutic implications. Mov Disord. 2013; 28:14–23.

2. Lücking CB, Dürr A, Bonifati V, Vaughan J, De Michele G, Gasser T, et al. Association between early-onset Parkinson's disease and mutations in the parkin gene. N Engl J Med. 2000; 342:1560–1567.

3. Periquet M, Latouche M, Lohmann E, Rawal N, De Michele G, Ricard S, et al. Parkin mutations are frequent in patients with isolated early-onset parkinsonism. Brain. 2003; 126(Pt 6):1271–1278.

4. Hedrich K, Marder K, Harris J, Kann M, Lynch T, Meija-Santana H, et al. Evaluation of 50 probands with early-onset Parkinson's disease for Parkin mutations. Neurology. 2002; 58:1239–1246.

5. Hedrich K, Eskelson C, Wilmot B, Marder K, Harris J, Garrels J, et al. Distribution, type, and origin of Parkin mutations: review and case studies. Mov Disord. 2004; 19:1146–1157.

6. Guo JF, Xiao B, Liao B, Zhang XW, Nie LL, Zhang YH, et al. Mutation analysis of Parkin, PINK1, DJ-1 and ATP13A2 genes in Chinese patients with autosomal recessive early-onset Parkinsonism. Mov Disord. 2008; 23:2074–2079.

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

8. Guo JF, Zhang XW, Nie LL, Zhang HN, Liao B, Li J, et al. Mutation analysis of Parkin, PINK1 and DJ-1 genes in Chinese patients with sporadic early onset parkinsonism. J Neurol. 2010; 257:1170–1175.

9. Zhang BR, Hu ZX, Yin XZ, Cai M, Zhao GH, Liu ZR, et al. Mutation analysis of parkin and PINK1 genes in early-onset Parkinson's disease in China. Neurosci Lett. 2010; 477:19–22.

10. Kim SY, Seong MW, Jeon BS, Kim SY, Ko HS, Kim JY, et al. Phase analysis identifies compound heterozygous deletions of the PARK2 gene in patients with early-onset Parkinson disease. Clin Genet. 2012; 82:77–82.

11. Chung EJ, Ki CS, Lee WY, Kim IS, Kim JY. Clinical features and gene analysis in Korean patients with early-onset Parkinson disease. Arch Neurol. 2006; 63:1170–1174.

12. Klein C, Pramstaller PP, Kis B, Page CC, Kann M, Leung J, et al. Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: expanding the phenotype. Ann Neurol. 2000; 48:65–71.

13. Kann M, Hedrich K, Vieregge P, Jacobs H, Müller B, Kock N, et al. The parkin gene is not involved in late-onset Parkinson's disease. Neurology. 2002; 58:835.

14. Lincoln SJ, Maraganore DM, Lesnick TG, Bounds R, de Andrade M, Bower JH, et al. Parkin variants in North American Parkinson's disease: cases and controls. Mov Disord. 2003; 18:1306–1311.

15. Clark LN, Afridi S, Karlins E, Wang Y, Mejia-Santana H, Harris J, et al. Case-control study of the parkin gene in early-onset Parkinson disease. Arch Neurol. 2006; 63:548–552.

16. Lesage S, Lohmann E, Tison F, Durif F, Dürr A, Brice A, et al. Rare heterozygous parkin variants in French early-onset Parkinson disease patients and controls. J Med Genet. 2008; 45:43–46.

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

18. Brooks J, Ding J, Simon-Sanchez J, Paisan-Ruiz C, Singleton AB, Scholz SW. Parkin and PINK1 mutations in early-onset Parkinson's disease: comprehensive screening in publicly available cases and control. J Med Genet. 2009; 46:375–381.

19. Pankratz N, Kissell DK, Pauciulo MW, Halter CA, Rudolph A, Pfeiffer RF, et al. Parkin dosage mutations have greater pathogenicity in familial PD than simple sequence mutations. Neurology. 2009; 73:279–286.

20. Kay DM, Stevens CF, Hamza TH, Montimurro JS, Zabetian CP, Factor SA, et al. A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2. Neurology. 2010; 75:1189–1194.

21. Wang C, Ma H, Feng X, Xie S, Chan P. Parkin dosage mutations in patients with early-onset sporadic and familial Parkinson's disease in Chinese: an independent pathogenic role. Brain Res. 2010; 1358:30–38.

22. Hughes AJ, Daniel SE, Lees AJ. Improved accuracy of clinical diagnosis of Lewy body Parkinson's disease. Neurology. 2001; 57:1497–1499.

23. Lesage S, Brice A. Parkinson's disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet. 2009; 18(R1):R48–R59.

24. Wu RM, Bounds R, Lincoln S, Hulihan M, Lin CH, Hwu WL, et al. Parkin mutations and early-onset parkinsonism in a Taiwanese cohort. Arch Neurol. 2005; 62:82–87.

25. Foroud T, Uniacke SK, Liu L, Pankratz N, Rudolph A, Halter C, et al. Heterozygosity for a mutation in the parkin gene leads to later onset Parkinson disease. Neurology. 2003; 60:796–801.

26. Sun M, Latourelle JC, Wooten GF, Lew MF, Klein C, Shill HA, et al. Influence of heterozygosity for parkin mutation on onset age in familial Parkinson disease: the GenePD study. Arch Neurol. 2006; 63:826–832.

27. Selikhova M, Williams DR, Kempster PA, Holton JL, Revesz T, Lees AJ. A clinico-pathological study of subtypes in Parkinson's disease. Brain. 2009; 132(Pt 11):2947–2957.

28. Hedrich K, Kann M, Lanthaler AJ, Dalski A, Eskelson C, Landt O, et al. The importance of gene dosage studies: mutational analysis of the parkin gene in early-onset parkinsonism. Hum Mol Genet. 2001; 10:1649–1656.

29. Brüggemann N, Mitterer M, Lanthaler AJ, Djarmati A, Hagenah J, Wiegers K, et al. Frequency of heterozygous Parkin mutations in healthy subjects: need for careful prospective follow-up examination of mutation carriers. Parkinsonism Relat Disord. 2009; 15:425–429.