Journal Article

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

Katja Hedrich, Martin Kann, Andrea J. Lanthaler, Andreas Dalski, Cordula Eskelson, Olfert Landt, Eberhard Schwinger, Peter Vieregge, Anthony E. Lang, Xandra O. Breakefield, Laurie J. Ozelius, Peter P. Pramstaller and Christine Klein

in Human Molecular Genetics

Volume 10, issue 16, pages 1649-1656
Published in print August 2001 | ISSN: 0964-6906
Published online August 2001 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/10.16.1649
The importance of gene dosage studies: mutational analysis of the parkin gene in early-onset parkinsonism

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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.

Journal Article.  4830 words.  Illustrated.

Subjects: Genetics and Genomics

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