Somatic and germline mosaicism in sporadic early-onset Alzheimer's disease
Somatic and germline mosaicism in sporadic early-onset Alzheimer's disease
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DOI：
10.1093/hmg/ddh134
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发表时间：
2004-06-15
影响因子：
3.5
通讯作者：
Tabrizi, SJ
中科院分区：
文献类型：
--
作者：
Beck, JA;Poulter, M;Tabrizi, SJ
阿尔茨海默病（AD）是世界上最常见的神经退行性疾病。罕见的家族性病例可能由淀粉样蛋白前体蛋白、早老素-1和早老素-2这三个基因中的一个突变引起；然而，99%的AD病例的分子基础是未知的。体细胞突变被认为是一种机制，可以解释散发性阿尔茨海默病的一部分，但迄今为止还没有证据证明这一点。我们现在报道了一例散发性早发性阿尔茨海默病患者，并表明该个体是早老素-1基因突变的体细胞嵌合体，这提示了一种新的阿尔茨海默病分子机制。嵌合性定量显示，指数患者外周血淋巴细胞嵌合度为8%，大脑皮层嵌合度为14%；基因剂量对发病年龄和临床表型表现有明显的影响。这一发现对散发性阿尔茨海默病的病因学以及其他明显散发性神经退行性疾病如帕金森病、运动神经元病和克雅氏病具有重要意义。
Alzheimer's disease (AD) is the commonest neurodegenerative disease worldwide. Rare familial cases may be caused by mutations in one of three genes-amyloid precursor protein, presenilin-1 and presenilin-2; however, the molecular basis of >99% of AD cases is unknown. Somatic mutation has been considered to be a mechanism that may account for a proportion of sporadic cases of AD, but to date there has been no evidence for this. We now report a sporadic early-onset patient with AD, and show that this individual is a somatic mosaic for a mutation in the presenilin-1 gene, suggesting a novel molecular mechanism for AD. Quantification of the mosaicism demonstrated the degree of mosaicism at 8% in peripheral lymphocytes and 14% in cerebral cortex in the index patient; a clear gene dosage effect on age of presentation and clinical phenotypic presentation is demonstrated. This finding has important implications for the aetiology of sporadic AD, and for other apparently sporadic neurodegenerative diseases such as Parkinson's disease, motor neuron disease and Creutzfeldt-Jakob disease.