Genomic investigation of α-synuclein multiplication and parkinsonism
Genomic investigation of α-synuclein multiplication and parkinsonism
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DOI：
10.1002/ana.21380
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发表时间：
2008-06-01
影响因子：
11.2
通讯作者：
Farrer, Matthew J.
中科院分区：
文献类型：
--
作者：
Ross, Owen A.;Braithwaite, Adam T.;Farrer, Matthew J.
目的：拷贝数变异是人类基因组中常见的多态现象。尽管这些事件大多数是无害的，但它们也可能具有高致病性。在此，我们描述了五个患有帕金森病的家族，这些家族已被鉴定为含有α-突触核蛋白基因（SNCA）的染色体4q21基因座的增殖。方法：使用荧光原位杂交和Affymetrix（加利福尼亚州圣克拉拉）250K SNP微阵列的方法学方法来表征每个家族中的增殖并鉴定该区域内编码的基因。使用微卫星标记的半定量聚合酶链反应进一步缩小每个家族的端粒和着丝粒断点，然后筛选转座重复元件。结果：临床表现的严重程度与 SNCA 剂量相关，并且似乎不受倍增区域中其他基因存在的明显影响。除了李斯特家族之外，每个家族中的倍增事件都是从头开始的。每个断点处的 Alu/LINE 重复序列的类型和位置也不同。微卫星分析表明，两种基因组机制导致染色体 4q21 倍增，包括 SNCA 复制和重组。解释：SNCA 剂量导致每个家族中观察到的帕金森病、自主神经功能障碍和痴呆症。我们假设野生型（α-突触核蛋白）表达失调会导致帕金森病，并可能解释最近常见 SNCA 变异与散发性帕金森病的关联。SNCA 基因组重复是由等位基因内（片段重复）或等位基因间重组与不等交换引起的，而这两种机制似乎都是基因组 SNCA 三倍体所需的。
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 a-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 telomeric 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 appear 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 appears 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 expression of wild-type (alpha-synuclein results in parkinsonism and may explain the recent association of common SNCA variants in sporadic Parkinson's disease. SNCA genomic duplication results from intraallelic (segmental duplication) or interallelic recombination with unequal crossing over, whereas both mechanisms appear to be required for genomic SNCA triplication.