Journal
HUMAN MUTATION
Volume 31, Issue 6, Pages 685-691Publisher
WILEY-BLACKWELL
DOI: 10.1002/humu.21248
Keywords
Parkinson; alpha-synuclein; SNCA; monoallelic; overexpression; epigenetic
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Funding
- Cyprus Research Promotion Foundation
- European Commission
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Genetic alterations in the alpha-synuclein (SNCA) gene have been implicated in Parkinson Disease (PD), including point mutations, gene multiplications, and sequence variations within the promoter. Such alterations may be involved in pathology through structural changes or overexpression of the protein leading to protein aggregation, as well as through impaired gene expression. It is, therefore, of importance to specify the parameters that regulate SNCA expression in its normal and mutated state. We studied the expression of SNCA alleles in a lymphoblastoid cell line and in the blood cells of a patient heterozygous for p.Ala53Thr, the first mutation to be implicated in PD pathogenesis. Here, we provide evidence that: (1) SNCA shows monoallelic expression in this patient, (2) epigenetic silencing of the mutated allele involves histone modifications but not DNA methylation, and (3) steady-state mRNA levels deriving from the normal SNCA allele in this patient exceed those of the two normal SNCA alleles combined, in matching, control individuals. An unbalanced SNCA expression in this patient is thus documented, with silencing of the p.A1a53Thr allele and upregulation of the wild-type-allele. This phenomenon is demonstrated for a first time in the SNCA gene, and may have important implications for PD pathogenesis. Hum Mutat 3 1:685-691, 2010. (C) 2010 Wiley-Liss, Inc.
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