Genomic investigation of α-synuclein multiplication and parkinsonism

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

Research output: Contribution to journalArticle

188 Citations (Scopus)

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 α-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 telometic 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 appeal 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 appeals 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 exptession 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 tesults from intraallelic (segmental duplication) ot intetallelic recombination with unequal crossing over, whereas both mechanisms appeal to be required for genomic SNCA triplication.

Original languageEnglish (US)
Pages (from-to)743-750
Number of pages8
JournalAnnals of Neurology
Volume63
Issue number6
DOIs
StatePublished - Jun 2008

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Synucleins
Parkinsonian Disorders
Microsatellite Repeats
Genetic Recombination
Genomic Segmental Duplications
Genes
DNA Transposable Elements
Human Genome
Fluorescence In Situ Hybridization
Single Nucleotide Polymorphism
Parkinson Disease
Dementia
Chromosomes
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Ross, O. A., Braithwaite, A. T., Skipper, L. M., Kachergus, J., Hulihan, M. M., Middleton, F. A., ... Farrer, M. J. (2008). Genomic investigation of α-synuclein multiplication and parkinsonism. Annals of Neurology, 63(6), 743-750. https://doi.org/10.1002/ana.21380

Genomic investigation of α-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; Maraganore, Demetrius M.; Adler, Charles Howard; Larvor, Lydie; Chartier-Harlin, Marie Christine; Nilsson, Christer; Langston, J. William; Gwinn, Katrina; Hattori, Nobutaka; Farrer, Matthew J.

In: Annals of Neurology, Vol. 63, No. 6, 06.2008, p. 743-750.

Research output: Contribution to journalArticle

Ross, OA, Braithwaite, AT, Skipper, LM, Kachergus, J, Hulihan, MM, Middleton, FA, Nishioka, K, Fuchs, J, Gasser, T, Maraganore, DM, Adler, CH, Larvor, L, Chartier-Harlin, MC, Nilsson, C, Langston, JW, Gwinn, K, Hattori, N & Farrer, MJ 2008, 'Genomic investigation of α-synuclein multiplication and parkinsonism', Annals of Neurology, vol. 63, no. 6, pp. 743-750. https://doi.org/10.1002/ana.21380
Ross OA, Braithwaite AT, Skipper LM, Kachergus J, Hulihan MM, Middleton FA et al. Genomic investigation of α-synuclein multiplication and parkinsonism. Annals of Neurology. 2008 Jun;63(6):743-750. https://doi.org/10.1002/ana.21380
Ross, Owen A ; Braithwaite, Adam T. ; Skipper, Lisa M. ; Kachergus, Jennifer ; Hulihan, Mary M. ; Middleton, Frank A. ; Nishioka, Kenya ; Fuchs, Julia ; Gasser, Thomas ; Maraganore, Demetrius M. ; Adler, Charles Howard ; Larvor, Lydie ; Chartier-Harlin, Marie Christine ; Nilsson, Christer ; Langston, J. William ; Gwinn, Katrina ; Hattori, Nobutaka ; Farrer, Matthew J. / Genomic investigation of α-synuclein multiplication and parkinsonism. In: Annals of Neurology. 2008 ; Vol. 63, No. 6. pp. 743-750.
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AU - Braithwaite, Adam T.

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AU - Middleton, Frank A.

AU - Nishioka, Kenya

AU - Fuchs, Julia

AU - Gasser, Thomas

AU - Maraganore, Demetrius M.

AU - Adler, Charles Howard

AU - Larvor, Lydie

AU - Chartier-Harlin, Marie Christine

AU - Nilsson, Christer

AU - Langston, J. William

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N2 - 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 α-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 telometic 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 appeal 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 appeals 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 exptession 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 tesults from intraallelic (segmental duplication) ot intetallelic recombination with unequal crossing over, whereas both mechanisms appeal to be required for genomic SNCA triplication.

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