Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia
Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia
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DOI：
10.1001/archneur.65.4.514
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发表时间：
2008-04-01
影响因子：
--
通讯作者：
Ishikawa, Atsushi
中科院分区：
文献类型：
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作者：
Ikeuchi, Takeshi;Kakita, Akiyoshi;Ishikawa, Atsushi
背景资料：α-突触核蛋白基因（SNCA）的增殖OMIM 163890）已被确定为遗传性帕金森病或路易体痴呆的致病突变。目的：确定尸检证实的常染色体显性路易体病患者的遗传、生化和神经病理学特征，特别是SNCA的剂量效应。设计：四代家庭研究。学术研究：患者：我们从4例患者的冷冻脑组织中提取样品进行生化表征，然后进行免疫印迹分析。主要结果测量：我们通过定量聚合酶链反应分析确定SNCA及其周围基因的剂量。结果：定量聚合酶链反应分析显示3例患者为SNCA重复杂合子，1例患者为SNCA重复纯合子。纯合子患者发病年龄早，死亡早，认知功能障碍较杂合子患者严重。生化分析表明，磷酸化的α-突触核蛋白积累在sarkosyl不溶性尿素提取馏分的patients.Conclusions的大脑：病理证实路易体病的临床特征为进行性帕金森综合征和认知功能障碍是由SNCA复制。纯合子患者表现出最严重的表型，表明SNCA剂量对疾病表型有相当大的影响，即使在一个家庭。SNCA复制导致患者脑中磷酸化α-突触核蛋白的过度积累。
Background: Multiplication of the alpha-synuclein gene (SNCA) (OMIM 163890) has been identified as a causative mutation in hereditary Parkinson disease or dementia with Lewy bodies.Objective: To determine the genetic, biochemical, and neuropathologic characteristics of patients with autopsy-confirmed autosomal dominant Lewy body disease, with particular reference to the dosage effects of SNCA.Design: Four-generation family study.Setting: Academic research.Patients: We fractionated samples extracted from frozen brain tissues of 4 patients for biochemical characterization, followed by immunoblot analysis.Main Outcome Measures: We determined the dosages of SNCA and its surrounding genes by quantitative polymerase chain reaction analysis.Results: Quantitative polymerase chain reaction analysis revealed that 3 patients were heterozygous for SNCA duplication and 1 patient was homozygous for SNCA duplication. The homozygous patient showed earlier age at onset and earlier death, with more severe cognitive impairment than the heterozygous patients. Biochemical analysis revealed that phosphorylated alpha-synuclein accumulated in the sarkosyl-insoluble urea-extracted fraction of the brains of the patients.Conclusions: Pathologically confirmed Lewy body disease clinically characterized by progressive parkinsonism and cognitive dysfunction is caused by SNCA duplication. The homozygous patient demonstrated the most severe phenotype, suggesting that SNCA dosage has a considerable effect on disease phenotype even within a family. SNCA duplication results in the hyperaccumulation of phosphorylated alpha-synuclein in the brains of patients.