Mutations in DJ-1 are less frequent than mutations in Parkin in EOPD patients but should be considered as a possible cause of EOPD. The effect of single heterozygous mutations in DJ-1 on the nigrostriatal system, as described for heterozygous changes in Parkin and PARK6, remains to be elucidated.

Recessively inherited early-onset parkinsonism (EOP) has been associated with mutations in the Parkin, DJ-1, and PINK1 genes. We studied the prevalence of mutations in all three genes in 65 Italian patients (mean age of onset: 43.275.4 years, 62 sporadic, three familial), selected by age at onset equal or younger than 51 years. Clinical features were compatible with idiopathic Parkinson's disease in all cases. To detect small sequence alterations in Parkin, DJ-1, and PINK1, we performed a conventional mutational analysis (SSCP/ dHPLC/sequencing) of all coding exons of these genes. To test for the presence of exon rearrangements in PINK1, we established a new quantitative duplex PCR assay. Gene dosage alterations in Parkin and DJ-1 were excluded using previously reported protocols. Five patients (8%; one woman/four men; mean age at onset: 38.279.7 (range 25-49) years) carried mutations in one of the genes studied: three cases had novel PINK1 mutations, one of which occurred twice (homozygous c.1602_1603insCAA; heterozygous c.1602_1603insCAA; heterozygous c.836G4A), and two patients had known Parkin mutations (heterozygous c.734A4T and c.924C4T; heterozygous c.924C4T). Family history was negative for all mutation carriers, but one with a history of tremor. Additionally, we detected one novel polymorphism (c.344A4T) and four novel PINK1 changes of unknown pathogenic significance (À21G/A; IVS1 þ 97A/G; IVS3 þ 38_40delTTT; c.852C4T), but no exon rearrangements. No mutations were found in the DJ-1 gene. The number of mutation carriers in both the Parkin and the PINK1 gene in our cohort is low but comparable, suggesting that PINK1 has to be considered in EOP.

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.

Four genes and six gene loci (PARK1-10) have been implicated in inherited forms of Parkinson's disease (PD). 1While the dominant forms appear to be very rare, recessively inherited types, such as parkin-associated PD, occur much more frequently.1 Recently, two recurrent heterozygous mutations in exon 1 of the NR4A2 gene, that encodes a member of the nuclear receptor superfamily essential for the differentiation of nigral dopaminergic neurons, have been found in 10 of 107 (9.3%) individuals with familial PD of European origin.2 Eight of the ten individuals carried the same mutation.2 Mode of inheritance appeared autosomal dominant in at least 8 of 10 cases, 2 suggesting that NR4A2 mutations may be a relatively frequent finding among patients with dominantly inherited PD. To evaluate the role of NR4A2 in our own European PD population with a positive family history (FH), we tested 50 PD patients with at least one first-degree relative affected with PD for sequence changes in exon 1 of NR4A2. Thirty-five of the 50 patients represent a subgroup of a previously described cohort of 111 community-derived PD patients and were selected for this study based on positive FH and absence of parkin mutations (see reference 3 for detailed clinical and genetic findings). The remaining 15 familial PD cases were referred to our movement disorders clinic. Polymerase chain reaction products of exon 1 of NR4A2 (305bp, spanning both known mutations) were directly sequenced. All cases (27 women 23 men; mean age at onset 41.8 Ϯ 11.5 years) fulfilled the current diagnostic criteria for idiopathic PD, except for the presence of a positive FH. Surprisingly, we did not detect either of the two known recurrent, nor any other mutation in the 100 alleles of our series. Our data suggest that NR4A2 mutations are less frequent than previously assumed, even if evidence for a common founder is considered in three of the European families described by Le et al.2 Supporting this notion, none of the recently published large genome scans for PD genes demonstrated linkage to the NR4A2 region, 4, and references herein while two of them showed linkage to the parkin region 4,5 and subsequently identified parkin mutations. In this context, the linkage study by Scott et al. is of particular interest, since it included many extended pedigrees rather than sibling pairs only, and is thus more likely to identify genes with dominantly acting mutations. 4,5 In conclusion, mutations in exon 1 of NR4A2 are not a major disease cause in European patients with familial PD. We read with interest the paper by Oliveira et al reporting results of a conventional mutational analysis of the parkin gene in a sample of 363 patients with Parkinson's disease (PD) from 307 families. 1 The authors found nine different mutations in 16 families (5%), 18% of which were present in their early-onset (EOPD Ͻ 40 years) and 2% in their late-onset PD cases (LOPD Ͼ 40 years), respectively.1 They described a detailed genotype/phenotype analysis demonstrating some significant differences amo...

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