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Human Molecular Genetics, 2001, Vol. 10, No. 16 1649-1656
© 2001 Oxford University Press

The importance of gene dosage studies: mutational analysis of the parkin gene in early-onset parkinsonism

Katja Hedrich1,2, Martin Kann1,2, Andrea J. Lanthaler1,2,3, Andreas Dalski2, Cordula Eskelson1,2, Olfert Landt4, Eberhard Schwinger2, Peter Vieregge1, Anthony E. Lang5, Xandra O. Breakefield6, Laurie J. Ozelius7, Peter P. Pramstaller8 and Christine Klein1,2,+

1Department of Neurology and 2Department of Human Genetics, Medical University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany, 3Department of Hematology, Regional General Hospital, 39100 Bolzano, Italy, 4TIB MOLBIOL, 10829 Berlin, Germany, 5Division of Neurology, Department of Medicine, University of Toronto, and Toronto Western Hospital, Toronto M5T 2S8, Canada, 6Molecular Neurogenetics Unit, Massachusetts General Hospital, and Departments of Neurology and Neuroscience Program, Harvard Medical School, Boston, MA 02129, USA, 7Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA and 8Department of Neurology, Regional General Hospital, 39100 Bolzano, Italy

Early-onset parkinsonism (EOP) may be associated with different mutations in the parkin gene, including exon deletions and duplications. To test for gene dosage alterations, we developed a new method of quantitative duplex PCR using the fluorescence resonance energy transfer technique on the LightCycler (Roche Diagnostics). In 21 patients with EOP, three mutations (a single base pair substitution in exon 3 and small deletions in exon 9) were detected by conventional mutational screening (single-strand conformation polymorphism and sequence analysis), while alterations of gene dosage were found in seven patients. We identified heterozygous and compound heterozygous deletions of exons 2, 3, 5 and 7. The latter was also found in the homozygous state. In addition, two heterozygous duplications of exon 4 were observed. Remarkably, two patients carried more than two parkin mutations. This is the first study systematically screening all 12 exons of parkin by real-time, kinetic quantification and clearly shows that mutational analysis of the parkin gene should include gene dosage studies. Furthermore, our method of quantitative PCR is easily applicable to any other gene to be screened for deletions or duplications of whole exons.

+ To whom correspondence should be addressed. Tel: +49 451 500 2993; Fax: +49 451 500 4861; Email: klein_ch@neuro.mu-luebeck.de The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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