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.
ASJC Scopus subject areas
- Clinical Neurology