β-Synuclein gene alterations in dementia with Lewy bodies
β-Synuclein gene alterations in dementia with Lewy bodies
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DOI：
10.1212/01.wnl.0000139870.14385.3c
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发表时间：
2004-09-14
期刊：
影响因子：
9.9
通讯作者：
La Spada, AR
中科院分区：
文献类型：
--
作者：
Ohtake, H;Limprasert, P;La Spada, AR
目的：确定α-突触核蛋白或β-突触核蛋白基因突变是否与路易体痴呆（DLB）有关，这是一种与帕金森病（PD）密切相关的疾病。方法：确定散发性DLB 33例，分离性DLB 10例.对来自43个指示病例的DNA样本进行了α-突触核蛋白和β-突触核蛋白基因改变的筛选，因为α-突触核蛋白改变导致PD，β-突触核蛋白可能调节α-突触核蛋白聚集和神经毒性。结果如下：在不相关的DLB指数病例中发现了两个氨基酸改变：密码子70（V70 M）处的缬氨酸至甲硫氨酸取代和密码子123（P123 H）处的脯氨酸至组氨酸取代，两者均在β-突触核蛋白基因中。这些氨基酸取代发生在β-突触核蛋白的高度保守区域中的保守残基处。从与患者人群组相匹配的对照受试者中筛选至少660条染色体，未能识别出另一个V70 M或P123 H等位基因。对分离P123 H β-突触核蛋白改变的扩展家系的共分离分析表明，P123 H β-突触核蛋白改变是一种显性性状，具有降低的遗传多态性或危险因子多态性。索引病例脑切片的组织病理学和免疫组织化学分析显示广泛的路易体病理学和α-突触核蛋白聚集，无β-突触核蛋白聚集的证据。结论：β-synuclein基因突变可能是DLB的易感基因。
Objective: To determine whether mutations in the genes for alpha-synuclein or beta-synuclein are responsible for dementia with Lewy bodies ( DLB), a disorder closely related to Parkinson disease (PD). Methods: The authors ascertained 33 sporadic cases of DLB and 10 kindreds segregating DLB. DNA samples from the 43 index cases were screened for alterations in the genes for alpha-synuclein and beta-synuclein, as alpha-synuclein alterations cause PD and beta-synuclein may modulate alpha-synuclein aggregation and neurotoxicity. Results: Two amino acid alterations were identified in unrelated DLB index cases: a valine to methionine substitution at codon 70 (V70M) and a proline to histidine substitution at codon 123 (P123H), both in the beta-synuclein gene. These amino acid substitutions occur at conserved residues in highly conserved regions of the beta-synuclein protein. Screening of at least 660 chromosomes from control subjects matched to the patients' population groups failed to identify another V70M or P123H allele. Cosegregation analysis of an extended pedigree segregating the P123H beta-synuclein alteration suggested that it is a dominant trait with reduced penetrance or a risk factor polymorphism. Histopathology and immunohistochemistry analysis of index case brain sections revealed widespread Lewy body pathology and alpha-synuclein aggregation without evidence of beta-synuclein aggregation. Conclusion: Mutations in the beta-synuclein gene may predispose to DLB.