Alpha-synuclein gene rearrangements in dominantly inherited parkinsonism: frequency, phenotype, and mechanisms.
OBJECTIVE
Genomic multiplications of the alpha-synuclein gene (SNCA) cause autosomal dominant Parkinson disease (ADPD). The aim of this study was to assess the frequency and phenotype of SNCA rearrangements in a large series of families with typical or atypical AD parkinsonism.


METHODS
Patients were screened by the exon dosage of the SNCA gene. The genotype of patients and relatives carrying SNCA rearrangements, the size of the multiplied regions, and the centromeric and telomeric breakpoints were determined by microsatellite dosage and 250K Affymetrix Single Polymorphism Nucleotide microarrays (Affymetrix, Santa Clara, California).


METHODS
Index cases and, whenever appropriate, relatives of 286 mainly European families with ADPD were screened.


RESULTS
Four of 264 families (1.5%) with typical ADPD carried duplications and 1 of 22 families (4.5%) with atypical AD parkinsonism carried a triplication of SNCA. Genotyping and dosage analyses showed that the multiplied regions were variable in size (0.42-5.29 megabase pairs), suggesting that SNCA multiplications occurred independently. Phenotype analyses showed that the severity of the disease correlated with the SNCA copy number, but not with the minimal number of multiplied genes (1 to 33). Haplotype analysis of polymorphic markers suggested that multiplication of the SNCA gene occurred by both interchromosomal and intrachromosomal rearrangement.


CONCLUSIONS
Our results suggest that SNCA rearrangements may be more frequent than point mutations in ADPD. Furthermore, our results indicate that the phenotype associated with SNCA multiplications correlates with the number of copies of the gene and provides the first insight into the mechanisms underlying SNCA multiplication.
Ibáñez
Pablo
P
Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé (UMR)_S679 Neurologie & Thérapeutique Expérimentale, F-75013, Paris, France.
Lesage
Suzanne
S
Janin
Sabine
S
Lohmann
Ebba
E
Durif
Frank
F
Destée
Alain
A
Bonnet
Anne-Marie
AM
Brefel-Courbon
Christine
C
Heath
Simon
S
Zelenika
Diana
D
Agid
Yves
Y
Dürr
Alexandra
A
Brice
Alexis
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001923:Brain Chemistry / Q000235:genetics*; D019457:Chromosome Breakage; D004252:DNA Mutational Analysis; D042622:DNA Repeat Expansion / Q000235:genetics; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D005799:Genes, Dominant / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics*
D051844:alpha-Synuclein