Alpha-synuclein gene rearrangements in dominantly inherited parkinsonism: frequency, phenotype, and mechanisms.

Pablo Ibáñez 1, 2 Suzanne Lesage 1 Sabine Janin 1 Ebba Lohmann 1 Frank Durif 3 Alain Destée 4 Anne-Marie Bonnet 1, 5 Christine Brefel-Courbon 6 Simon Heath 7 Diana Zelenika 7 Yves Agid 1, 5 Alexandra Dürr 1, 8 Alexis Brice 1, 8, 9, *
* Auteur correspondant
1 Neurologie et thérapeutique expérimentale
2 Wellcome Trust Centre for Gene Regulation and Expression
3 Service de neurologie
4 Service de neurochirurgie générale et stéréotaxique fonctionnelle
5 Department of Nervous system Disorders
6 Service de Pharmacologie Médicale et Clinique
7 CNG - Centre National de Génotypage
8 Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière]
9 Department of the Central Nervous System Disorders
Abstract : 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. 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.
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Article dans une revue
Archives of Neurology -Chigago-, American Medical Association, 2009, 66 (1), pp.102-8. 〈10.1001/archneurol.2008.555〉
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Soumis le : lundi 25 octobre 2010 - 11:51:20
Dernière modification le : mercredi 5 septembre 2018 - 15:32:02

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Pablo Ibáñez, Suzanne Lesage, Sabine Janin, Ebba Lohmann, Frank Durif, et al.. Alpha-synuclein gene rearrangements in dominantly inherited parkinsonism: frequency, phenotype, and mechanisms.. Archives of Neurology -Chigago-, American Medical Association, 2009, 66 (1), pp.102-8. 〈10.1001/archneurol.2008.555〉. 〈inserm-00529237〉

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