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From the Departments of Neurology (K. Hedrich, M. Kann, and Dr. Klein) and Human Genetics (K. Hedrich, M. Kann, and Drs. Schwinger and Klein), Medical University of Lübeck, Germany; Department of Neurology (Drs. Marder, Harris, Lynch, and Fahn, and H. Meija–Santana), Columbia University, Gertrude H. Sergievsky Center (Drs. Marder and Meija–Santana), and Taub Institute for Research on Alzheimer’s disease and the Aging Brain (Dr. Marder), New York, NY; University College (Dr. Lynch), Dublin, Ireland; Department of Neurology (Dr. Pramstaller), Regional General Hospital, Bolzano, Italy; and Department of Neurology (Dr. Bressman), Albert Einstein College of Medicine, Bronx, NY.
Address correspondence and reprint requests to Dr. Christine Klein, Department of Neurology, Medical University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany; e-mail: klein_ch{at}neuro.mu-luebeck.de
Background: Early onset PD has been associated with different mutations in the Parkin gene, including exon deletions and duplications.
Methods: The authors performed an extensive mutational analysis on 50 probands with onset of PD at younger than 50 years of age. Thirteen probands were ascertained from a registry of familial PD and 37 probands by age at onset at younger than 50 years, blind to family history. Mutational analysis was undertaken on the probands and available family members and included conventional techniques (single strand conformation polymorphism analysis and sequencing) and a newly developed method of quantitative duplex PCR to detect alterations of gene dosage (exon deletions and duplications) in Parkin.
Results: Using this new technique, the authors detected eight alterations of gene dosage in the probands, whereas 12 mutations were found by conventional methods among the probands and another different mutation in an affected family member. In total, the authors identified compound heterozygous mutations in 14%, heterozygous mutations in 12%, and no Parkin mutation in 74% of the 50 probands. We expanded the occurrence of Parkin mutations to another ethnic group (African-American).
Conclusion: The authors systematically screened all 12 Parkin exons by quantitative PCR and conventional methods in 50 probands. Eight mutations were newly reported, 2 of which are localized in exon 1, and 38% of the mutations were gene dosage alterations. These results underline the need to screen all exons and to undertake gene dosage studies. Furthermore, this study reveals a frequency of heterozygous mutation carriers that may signify a unique mode of inheritance and expression of the Parkin gene.
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