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-Synuclein Gene Rearrangements in Dominantly Inherited Parkinsonism

Frequency, Phenotype, and Mechanisms

Pablo Ibáñez, PhD; Suzanne Lesage, PhD; Sabine Janin, BS; Ebba Lohmann, MD; Frank Durif, MD; Alain Destée, MD; Anne-Marie Bonnet, MD; Christine Brefel-Courbon, MD; Simon Heath, PhD; Diana Zelenika, PhD; Yves Agid, MD, PhD; Alexandra Dürr, MD, PhD; Alexis Brice, MD; for the French Parkinson's Disease Genetics Study Group

Arch Neurol. 2009;66(1):102-108.

Objective  Genomic multiplications of the -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.

Design  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).

Subjects  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.

Author Affiliations: 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 (Drs Ibáñez, Lesage, Lohmann, Bonnet, Agid, Dürr, and Brice and Ms Janin); Université Pierre et Marie Curie (UPMC) Univ Paris 06, UMR_S679, F-75005, Paris, France (Drs Ibáñez, Lesage, Lohmann, Bonnet, Agid, Dürr, and Brice and Ms Janin); Wellcome Trust Centre for Gene Regulation and Expression, University of Dundee, Dundee, Scotland (Dr Ibáñez); Equipe Mixte INSERM (EMI)–INSERM 9904, Service de Neurologie, Hôpital Gabriel Montpied, Clermont-Ferrand, France (Dr Durif); Equipe d'Accueil (EA) 2683, Service de Neurologie, Hôpital R. Salengro, Centre Hospitalier Régional Universitaire de Lille, Lille, France (Dr Destée); Assistance Publique–Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Department of Nervous System Disorders, F-75013, Paris, France (Drs Bonnet and Agid); Centre d’Investigation Clinique, Service de Pharmacologie Médicale et Clinique, Faculté de Médecine, Centre Hospitalier Universitaire Toulouse, Toulouse, France (Dr Brefel-Courbon); Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (Drs Heath and Zelenika); and AP-HP, Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics, F-75013, Paris, France (Drs Dürr and Brice).

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