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Genomic investigation of alpha-synuclein multiplication and parkinsonism

Ross, Owen A.; Braithwaite, Adam T.; Skipper, Lisa M.; Kachergus, Jennifer; Hulihan, Mary M.; Middleton, Frank A.; Nishioka, Kenya; Fuchs, Julia; Gasser, Thomas and Maraganore, Demetrius M., et al. (2008) In Annals of Neurology 63(6). p.743-750
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 a-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... (More)
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 a-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. (Less)
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publication status
published
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in
Annals of Neurology
volume
63
issue
6
pages
743 - 750
publisher
John Wiley and Sons Inc.
external identifiers
  • wos:000257294100007
  • scopus:46749144187
ISSN
1531-8249
DOI
10.1002/ana.21380
language
English
LU publication?
yes
id
fb647e5a-b642-412b-90bd-9f4f94981c57 (old id 1257164)
date added to LUP
2008-10-14 15:39:35
date last changed
2017-09-24 03:34:12
@article{fb647e5a-b642-412b-90bd-9f4f94981c57,
  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 a-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.},
  author       = {Ross, Owen A. and Braithwaite, Adam T. and Skipper, Lisa M. and Kachergus, Jennifer and Hulihan, Mary M. and Middleton, Frank A. and Nishioka, Kenya and Fuchs, Julia and Gasser, Thomas and Maraganore, Demetrius M. and Adler, Charles H. . and Larvor, Lydie and Chartier-Harlin, Marie-Christine and Nilsson, Christer and Langston, J. William and Gwinn, Katrina and Hattori, Nobutaka and Farrer, Matthew J.},
  issn         = {1531-8249},
  language     = {eng},
  number       = {6},
  pages        = {743--750},
  publisher    = {John Wiley and Sons Inc.},
  series       = {Annals of Neurology},
  title        = {Genomic investigation of alpha-synuclein multiplication and parkinsonism},
  url          = {http://dx.doi.org/10.1002/ana.21380},
  volume       = {63},
  year         = {2008},
}