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From the Departments of Human Genetics (Drs. Hedrich, Schwinger, and Klein, and A. Djarmati, N. Schäfer, and C. Wellenbrock) and Neurology (Drs. Hedrich, Vieregge, and Klein, and A. Djarmati, N. Schäfer, and C. Wellenbrock), University of Lübeck, Germany; Faculty of Biology (A. Djarmati), University of Belgrade, Serbia; Department of Medical Genetics (Drs. Hering and Riess), University Tübingen, Germany; Department of Neurology (Drs. Weiss and Noth), University of Aachen, Germany; Department of Neurology (Dr. Hilker), University of Cologne, Germany; Department of Molecular Genetics (Dr. Ozelius), Albert Einstein College of Medicine, Bronx, NY; Genetic-Epidemiologic Unit (Drs. Heutink and Bonifati), Department of Clinical Genetics, Department of Epidemiology & Biostatistics, Eramus Medical Center Rotterdam, the Netherlands; Department of Neurological Sciences (Dr. Bonifati), "La Sapienza" University, Rome, Italy; Division of Neurology (Dr. Lang), Department of Medicine, University of Toronto, and Toronto Western Hospital, Canada; Department of Neurology (Dr. Bressman), Beth Israel Medical Center, New York, NY; and Department of Neurology (Dr. Pramstaller), Regional General Hospital, Bolzano, Italy.
Address correspondence and reprint requests to Dr. Christine Klein, Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany; e-mail: klein_ch{at}neuro.mu-luebeck.de
Background: Mutations in the Parkin gene (PARK2) are the most commonly identified cause of recessively inherited early-onset Parkinson disease (EOPD) but account for only a portion of cases. DJ-1 (PARK7) was recently reported as a second gene associated with recessively inherited PD with a homozygous exon deletion and a homozygous point mutation in two families.
Methods: To investigate the frequency of DJ-1 mutations, the authors performed mutational analysis of all six coding exons of DJ-1 in 100 EOPD patients. For the detection of exon rearrangements, the authors developed a quantitative duplex PCR assay. Denaturing high performance liquid chromatography analysis was used to screen for point mutations and small deletions. Further, Parkin analysis was performed as previously described.
Results: The authors identified two carriers of single heterozygous loss-of-function DJ-1 mutations, including a heterozygous deletion of exons 5 to 7 and an 11-base pair deletion, removing the invariant donor splice site in intron 5. Interestingly, both DJ-1 mutations identified in this study were found in the heterozygous state only. The authors also detected a polymorphism (R98Q) in 1.5% of the chromosomes in both the patient and control group. In the same patient sample, 17 cases were detected with mutations in the Parkin gene.
Conclusions: 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.
Received July 25, 2003. Accepted in final form December 4, 2003.
*The first two authors contributed equally to this study.
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