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Genomic investigation of α‐synuclein multiplication and parkinsonism
Author(s) -
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 H.,
Larvor Lydie,
ChartierHarlin MarieChristine,
Nilsson Christer,
Langston J. William,
Gwinn Katrina,
Hattori Nobutaka,
Farrer Matthew J.
Publication year - 2008
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21380
Subject(s) - genetics , gene duplication , biology , copy number variation , comparative genomic hybridization , locus (genetics) , breakpoint , parkinsonism , alu element , gene , genome , chromosome , human genome , disease , medicine , pathology
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 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 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