Genomic investigation of α-synuclein multiplication and parkinsonism
Article first published online: 20 JUN 2008
Copyright © 2008 American Neurological Association
Annals of Neurology
Volume 63, Issue 6, pages 743–750, June 2008
How to Cite
Ross, O. A., Braithwaite, A. T., Skipper, L. M., Kachergus, J., Hulihan, M. M., Middleton, F. A., Nishioka, K., Fuchs, J., Gasser, T., Maraganore, D. M., Adler, C. H., Larvor, L., Chartier-Harlin, M.-C., Nilsson, C., Langston, J. W., Gwinn, K., Hattori, N. and Farrer, M. J. (2008), Genomic investigation of α-synuclein multiplication and parkinsonism. Ann Neurol., 63: 743–750. doi: 10.1002/ana.21380
- Issue published online: 20 JUN 2008
- Article first published online: 20 JUN 2008
- Manuscript Accepted: 11 FEB 2008
- Manuscript Revised: 29 JAN 2008
- Manuscript Received: 8 NOV 2007
- American Parkinson Disease Association
- Morris K. Udall Parkinson's Disease Research Center of Excellence (National Institute of Neurological Disorders and Stroke). Grant Number: P50 #NS40256
- NIH (National Institute of Aging). Grant Number: P01 #AG17216
- German National Genome Network (NGFN). Grant Number: 01GS0116
- PHRC 2005/1914 the Universite de Lille 2 and Institut National de la Sante et de la Recherche Medicale
- Draper Family Foundation
- NIH (National Institute of Neurological Disorders and Stroke). Grant Number: #N01-NS-2-2349
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 α-synuclein gene (SNCA).
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.
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.
SNCA dosage is responsible for parkinsonism, autonomic dysfunction, and dementia observed within each family. We hypothesize dysregulated expression of wild-type α-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. Ann Neurol 2008