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. 2014 Jul;29(8):1060-4.
doi: 10.1002/mds.25883. Epub 2014 Apr 21.

Analysis of Parkinson's disease brain-derived DNA for alpha-synuclein coding somatic mutations

Christos Proukakis  1 , Maryiam Shoaee, James Morris, Timothy Brier, Eleanna Kara, Una-Marie Sheerin, Gavin Charlesworth, Eduardo Tolosa, Henry Houlden, Nicholas W Wood, Anthony H Schapira
Affiliations
Free PMC article

Analysis of Parkinson's disease brain-derived DNA for alpha-synuclein coding somatic mutations

Christos Proukakis et al. Mov Disord. 2014 Jul.
Free PMC article

Abstract

Background: Although alpha-synuclein (SNCA) is crucial to the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), mutations in the gene appear to be rare. We have recently hypothesized that somatic mutations in early development could contribute to PD.

Methods: Expanding on our recent negative small study, we used high-resolution melting (HRM) analysis to screen SNCA coding exons for somatic point mutations in DNA from 539 PD and DLB cerebellar samples, with two additional regions (frontal cortex, substantia nigra) for 20 PD cases. We used artificial mosaics to determine sensitivity where possible.

Results: We did not detect any evidence of somatic coding mutations. Three cases were heterozygous for known silent polymorphisms. The protocol we used was sensitive enough to detect 5% to 10% mutant DNA.

Conclusion: Using DNA predominantly from cerebellum, but also from frontal cortex and substantia nigra (n = 20 each), we have not detected any somatic coding SNCA point mutations.

Keywords: SNCA; alpha-synuclein; etiology of Parkinson's disease; mosaicism; somatic mutation.

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Figures

Figure 1
Figure 1
Estimation of sensitivity of HRM for detection of low levels of exon 3 SNV. A: H50Q, B: A53T, C: G51D. The undiluted heterozygous sample (50% mutation) is blue and identified by arrows, and lower levels of mutations are 20% (red), 10% (green), 5% (orange), 2.5% (purple, identified by arrowheads). Controls are shown in gray. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]
Figure 2
Figure 2
Estimation of sensitivity of HRM for detection of low levels of SNV in other exons. A: rs144758871 (exon 4), B: rs76642636 (exon 6). The undiluted heterozygous sample (50% SNV) is blue, and SNV levels in diluted samples are 20% (red), 10% (green), 5% (orange), 2.5% (purple). Controls are shown in gray. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]
See this image and copyright information in PMC

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