Reznik-Wolf H, Machado J, Haroutunian V, DeMarco L, Walter G F, Goldman B, Davidson M, Johnston J A, Lannfelt L, Dani S U, Friedman E
Institute of Genetics, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
J Neurogenet. 1998 Jan;12(1):55-65. doi: 10.3109/01677069809108555.
The molecular basis for sporadic Alzheimer disease (AD) remains largely unknown. We hypothesized that in some cases of sporadic AD, a somatic mutation in an embryonic cell committed to neuronal development within the amyloid precursor protein (APP), the presenilin 1 (PS-1) or the presenilin 2 (PS-2) genes (genes known to be involved in familial AD) may result in AD phenotype. Using PCR, denaturing gradient gel electrophoresis (DGGE), restriction enzyme digest and direct DNA sequencing, we analyzed these genes in 99 brain tissues from patients with histopathologically proven AD. One brain sample showed a mutation within the PS-1 gene, His163 Arg, later shown to be a germline mutation. No other migration abnormalities were demonstrated in any sample in exon 16 or 17 of the APP gene or the coding exons of the PS-1 gene. Restriction digest pattern was normal with regard to the predominant PS-2 gene mutation (N141I). A known mutation in the APP gene, as well as novel mutations within the PS-1 gene were easily detected by DGGE (Reznick Wolf et al. manuscript submitted). We conclude that the genes that are involved in familial AD do not display somatic mutations in the brains of sporadic AD patients, and that other molecular mechanisms are probably involved in the pathogenesis of sporadic AD.
散发性阿尔茨海默病（AD）的分子基础在很大程度上仍不清楚。我们推测，在某些散发性AD病例中，淀粉样前体蛋白（APP）、早老素1（PS-1）或早老素2（PS-2）基因（已知与家族性AD相关的基因）中致力于神经元发育的胚胎细胞发生体细胞突变，可能导致AD表型。我们使用聚合酶链反应（PCR）、变性梯度凝胶电泳（DGGE）、限制性内切酶消化和直接DNA测序，对99例经组织病理学证实为AD患者的脑组织中的这些基因进行了分析。一个脑样本显示PS-1基因内存在突变，即His163 Arg，后来证明是种系突变。在APP基因的第16或17外显子或PS-1基因的编码外显子的任何样本中，均未发现其他迁移异常。关于主要的PS-2基因突变（N141I），限制性消化模式正常。通过DGGE很容易检测到APP基因中的已知突变以及PS-1基因内的新突变（Reznick Wolf等人的手稿已提交）。我们得出结论，与家族性AD相关的基因在散发性AD患者的大脑中未显示体细胞突变，并且其他分子机制可能参与散发性AD的发病机制。
