Genomic investigation of alpha-synuclein multiplication and parkinsonism.
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 alpha-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.


CONCLUSIONS
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.
Division of Neurogenetics, Department of Neuroscience, College of Medicine, Mayo Clinic, Jacksonville, FL 32224, USA.
Owen A
OA
Ross
Adam T
AT
Braithwaite
Lisa M
LM
Skipper
Jennifer
J
Kachergus
Mary M
MM
Hulihan
Frank A
FA
Middleton
Kenya
K
Nishioka
Julia
J
Fuchs
Thomas
T
Gasser
Demetrius M
DM
Maraganore
Charles H
CH
Adler
Lydie
L
Larvor
Marie-Christine
MC
Chartier-Harlin
Christer
C
Nilsson
J William
JW
Langston
Katrina
K
Gwinn
Nobutaka
N
Hattori
Matthew J
MJ
Farrer
D000328:Adult; D000368:Aged; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D016678:Genome / Q000235:genetics; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
D051844:alpha-Synuclein