Genomic investigation of α‐synuclein multiplication and parkinsonism

• DOI: 10.1002/ana.21380
• Publication Date: 2008-06-20T16:07:34Z
• Authors: 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. Mara...; Charles H. Adler; Lydie Larvor; Marie‐Christine C...; Christer Nilsson; J. William Langston; Katrina Gwinn; Nobutaka Hattori; Matthew J. Farrer
• Keywords: Comparative genomic hybridization; Breakpoint; Alu element

Copy number variation is a common polymorphic phenomenon within the human genome. Although 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 chromosomal 4q21 locus containing alpha-synuclein gene (SNCA).A methodological approach using fluorescent in situ hybridization and Affymetrix (Santa Clara, CA) 250K SNP microarrays was used each family identify genes encoded region. The telomeric centromeric breakpoints were further narrowed semiquantitative polymerase chain reaction microsatellite markers then screened for transposable repeat elements.The severity clinical presentation correlated SNCA dosage does not appear overtly affected by presence other multiplicated With exception Lister kindred, event appears de novo. type position Alu/LINE repeats different at breakpoint. Microsatellite analysis demonstrates two genomic mechanisms responsible chromosome multiplications, including both duplication recombination.SNCA parkinsonism, autonomic dysfunction, dementia observed family. We hypothesize dysregulated expression wild-type results may explain recent association variants sporadic Parkinson's disease. from intraallelic (segmental duplication) or interallelic recombination unequal crossing over, whereas required triplication.