Genomic investigation of alpha-synuclein multiplication and parkinsonism - PubMed (original) (raw)

Adam T Braithwaite, Lisa M Skipper, Jennifer Kachergus, Mary M Hulihan, Frank A Middleton, Kenya Nishioka, Julia Fuchs, Thomas Gasser, Demetrius M Maraganore, Charles H Adler, Lydie Larvor, Marie-Christine Chartier-Harlin, Christer Nilsson, J William Langston, Katrina Gwinn, Nobutaka Hattori, Matthew J Farrer

Affiliations

Genomic investigation of alpha-synuclein multiplication and parkinsonism

Owen A Ross et al. Ann Neurol. 2008 Jun.

Abstract

Objective: Copy number variation is a common polymorphic phenomenon within the human genome. Although the majority of these events are non-deleterious they can also be highly pathogenic. Herein we characterize five families with parkinsonism that have been identified to harbor multiplication of the chromosomal 4q21 locus containing the alpha-synuclein gene (SNCA).

Methods: A methodological approach using fluorescent in situ hybridization and Affymetrix (Santa Clara, CA) 250K SNP microarrays was used to characterize the multiplication in each family and to identify the genes encoded within the region. The telomeric and centromeric breakpoints of each family were further narrowed using semiquantitative polymerase chain reaction with microsatellite markers and then screened for transposable repeat elements.

Results: The severity of clinical presentation is correlated with SNCA dosage and does not appear to be overtly affected by the presence of other genes in the multiplicated region. With the exception of the Lister kindred, in each family the multiplication event appears de novo. The type and position of Alu/LINE repeats are also different at each breakpoint. Microsatellite analysis demonstrates two genomic mechanisms are responsible for chromosome 4q21 multiplications, including both SNCA duplication and recombination.

Interpretation: SNCA dosage is responsible for parkinsonism, autonomic dysfunction, and dementia observed within each family. We hypothesize dysregulated expression of wild-type alpha-synuclein results in parkinsonism and may explain the recent association of common SNCA variants in sporadic Parkinson's disease. SNCA genomic duplication results from intraallelic (segmental duplication) or interallelic recombination with unequal crossing over, whereas both mechanisms appear to be required for genomic SNCA triplication.

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Conflict of interest statement

The authors declare no financial or other conflicts of interest.

Figures

Figure 1

Figure 1. FISH and CHIPs

A representation of fluorescent in-situ hybridization (FISH) and Affymetrix 250k SNP microarrays (CHIPS) that were used to examine the region of multiplication in the proband of each family. (a) Relative copy number estimates were plotted against physical genomic position on chromosome 4. Raw data is shown that has not been normalized with respect to integers. (b) FISH was performed on interphase cells with three labeled SNCA probes directed at the entire locus (PAC 27M07 in GREEN), with promoter and intron 4 fragments (visualized in RED). SNCA multiplication was confirmed in all samples using both methodologies.

Figure 2

Figure 2. A representation of the genes in the multiplication region in each family

Displays the genes that are present in each of the multiplied regions of the families. The figure is drawn approximately to scale. The coding genomic DNA strand of each gene is indicated by (+) or (−). Genes are colored to represent their relative expression in brain according to the GNF Expression Atlas 2 (

http://genome.ucsc.edu/

), with red, black and green representing high, medium and low expression respectively. Gene symbols in gray text indicate hypothetical genes. The gray bars below the chromosome diagram show the regions of multiplication in each family.

Figure 3

Figure 3. Legend

The allele sizes and dosage for the chromosome 4 markers D4S3476, D4S3479 and D4S3474 are shown for each family. These data demonstrate an intra-allelic, segmental duplication in the French and Japanese-A families. However inter-allelic recombination occurred initially in Japanese-B and the in Lister kindred duplication, indicated by the presence of three different alleles at marker D4S3476 (163, 167 & 169)(a). A further segmental duplication is apparent in the Lister kindred branch with SNCA triplication (b). It is not possible to ascertain the sequence of events for the SNCA triplication in the Iowa kindred but the presence of three alleles sizes at all markers demonstrates a recombination event must have occurred.

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References

    1. Simon-Sanchez J, Scholz S, Fung HC, et al. Genome-wide SNP assay reveals structural genomic variation, extended homozygosity and cell-line induced alterations in normal individuals. Hum Mol Genet. 2007;16:1–14. - PubMed
    1. Redon R, Ishikawa S, Fitch KR, et al. Global variation in copy number in the human genome. Nature. 2006;444:444–454. - PMC - PubMed
    1. Wong KK, Deleeuw RJ, Dosanjh NS, et al. A comprehensive analysis of common copy-number variations in the human genome. Am J Hum Genet. 2007;80:91–104. - PMC - PubMed
    1. Singleton AB, Farrer M, Johnson J, et al. alpha-Synuclein locus triplication causes Parkinson's disease. Science. 2003;302:841. - PubMed
    1. Chartier-Harlin MC, Kachergus J, Roumier C, et al. Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet. 2004;364:1167–1169. - PubMed

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