Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease
Identification of independent APP locus duplication in Japanese patients with early-onset Alzheimer disease
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DOI：
10.1136/jnnp.2008.161703
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发表时间：
2009-09-01
影响因子：
11
通讯作者：
Ikeuchi, T.
中科院分区：
文献类型：
--
作者：
Kasuga, K.;Shimohata, T.;Ikeuchi, T.
背景：在患有早发家族性阿尔茨海默病（EO-FAD）和脑淀粉样血管病的欧洲家庭中已经描述了淀粉样前体蛋白基因（APP）重复的发生。然而，APP 重复对其他种族人群中 AD 发展的贡献仍未确定。方法：通过定量 PCR 和基于微阵列的比较基因组杂交分析，检查了日本人群中 25 个 FAD 家庭的先证者和 11 个散发性 EO-AD 病例中 APP 重复的发生情况。使用从患者外周血中提取的 mRNA，通过实时定量逆转录 (RT) PCR 分析来确定 APP 表达水平。结果：我们在两个不相关的 EO-FAD 家族中发现了 APP 基因座重复。这些家族的两名患者的重复基因组区域彼此不同。在晚发FAD家族或散发性EO-AD患者中未发现APP重复。 APP重复的患者在50多岁时出现隐性记忆障碍，但没有脑出血和癫痫。定量RT-PCR分析显示，与年龄和性别匹配的对照相比，这些患者的APP mRNA表达水平升高。结论：我们的结果表明，不同种族的EO-FAD患者应考虑APP重复，并且APP重复导致的APP mRNA表达水平升高有助于AD的发展。
Background: The occurrence of duplications of the amyloid precursor protein gene (APP) has been described in European families with early-onset familial Alzheimer disease (EO-FAD) and cerebral amyloid angiopathy. However, the contribution of APP duplication to the development of AD in other ethnic populations remains undetermined.Methods: The occurrence of APP duplication in probands from 25 families with FAD and 11 sporadic EO-AD cases in the Japanese population was examined by quantitative PCR and microarray-based comparative genomic hybridisation analyses. APP expression level was determined by real-time quantitative reverse-transcription (RT) PCR analysis using mRNA extracted from the peripheral blood of the patients.Results: We identified APP locus duplications in two unrelated EO-FAD families. The duplicated genomic regions in two patients of these families differed from each other. No APP duplication was found in the late-onset FAD families or sporadic EO-AD patients. The patients with APP duplication developed insidious memory disturbance in their fifties without intracerebral haemorrhage and epilepsy. Quantitative RT-PCR analysis showed the increased APP mRNA expression levels in these patients compared with those in age- and sex-matched controls.Conclusions: Our results suggest that APP duplication should be considered in patients with EO-FAD in various ethnic groups, and that increased APP mRNA expression level owing to APP duplication contributes to AD development.