Detection ofParkin(PARK2) andDJ1(PARK7) mutations in early-onset Parkinson disease:Parkinmutation frequency depends on ethnic origin of patients

Abstract

Mutations in the Parkin (PARK2) and the DJ1 (PARK7) gene cause early-onset Parkinson disease (EOPD). We tested 75 Serbian EOPD patients for mutations in both genes by conventional mutational screening (SSCP/dHPLC/sequencing) to detect small sequence alterations and by gene dosage studies (quantitative PCR) to reveal deletions or multiplications of one or more exons. A compound heterozygous Parkin mutation (exon deletion and point mutation; [c.836_972del]+[c.1411C>T]; +1 is first nucleotide of GenBank AB009973.1) was identified in a patient who showed a relatively benign course after a disease onset at 41 years. Another case had a heterozygous exon deletion in DJ1 ([c.253_322del]+[?]) and presented with an age at onset of 45 years and a rapid disease course. In conclusion, Parkin mutations are surprisingly rare in our Serbian EOPD sample, suggesting that the mutation rate depends on the ethnic origin of the patients. Although DJ1 mutations appear to be rare, we confirm their role in EOPD and demonstrate the importance of gene dosage studies.

PINK1, Parkin, and DJ-1 mutations in Italian patients with early-onset parkinsonism

“…14 Our study design and the results are compatible with those from the recently published study on Italian EOP patients 10 and suggest that the frequency of PINK1 mutations may be comparable to that of Parkin mutations in patients with mainly sporadic EOP, at least in some populations. The prevalence of detected Parkin mutations was low but still in keeping with previous studies on ethnically homogeneous patient samples, 8,18 particularly in sporadic patients. Technical reasons explaining the low mutation rate in the present sample are unlikely, since we employed a comprehensive genetic screening method.…”

“…6,27,28 With regard to the DJ-1 gene, recent studies demonstrated a mutation frequency between 1 and 2% among EOP patients. 7,8,15,16 Only two of the published investigations included testing for gene dosage alterations and, as expected, revealed higher mutation rates (2 versus 1%). 7,8 However, based on those previous investigations, one would only expect one DJ-1 mutation carrier in our 65 study subjects, and the present study confirms the notion that DJ-1 mutations are a rare cause of EOP.…”

“…6 For the recently identified PINK1 gene, only point mutations and one four-nucleotide insertion have been reported to date. 2,10 -14 While the frequency of Parkin mutations in EOP patients has been estimated at 10 -25%, 5 and DJ-1 mutations account for 1% 15,16 to 2% 7,8 of the tested EOP cases, the frequency of mutations in PINK1 still remains to be accurately determined. Although a first study suggested a frequency of 7%, including patients with heterozygous mutations, 10 recent findings revealed that the PINK1 mutation rate is much lower in an Irish PD population.…”

“…5 Ethnic background of the patients also affects the mutation rate with frequencies of Parkin mutations ranging from 66% in patients from Japan 17 to less than 4% in a US or Serbian EOP population. 8,18 However, such diverse findings may be the result of referral bias at specialty centers, attracting a higher number of patients with a positive family history, suggestive of a genetic cause. Finally, the rate of detected mutations is dependent on the extent of the mutational analysis performed.…”

Genetics of Parkinson’s Disease: The Role of Copy Number Variations

“…Further heterozygous CNVs (both deletions and duplication) involving the exons of DJ-1 gene have been published so far [93,[100][101][102], although they do not completely explain the recessive pattern of the PD phenotype.…”