Maruszak Aleksandra, Safranow Krzysztof, Gustaw Katarzyna, Kijanowska-Haładyna Beata, Jakubowska Katarzyna, Olszewska Maria, Styczyńska Maria, Berdyński Mariusz, Tysarowski Andrzej, Chlubek Dariusz, Siedlecki Janusz, Barcikowska Maria, Zekanowski Cezary
Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warszawa, Poland.
BMC Med Genet. 2009 Nov 12;10:115. doi: 10.1186/1471-2350-10-115.
Peptidyl-prolyl isomerase, NIMA-interacting 1 (PIN1) plays a significant role in the brain and is implicated in numerous cellular processes related to Alzheimer's disease (AD) and other neurodegenerative conditions. There are confounding results concerning PIN1 activity in AD brains. Also PIN1 genetic variation was inconsistently associated with AD risk.
We performed analysis of coding and promoter regions of PIN1 in early- and late-onset AD and frontotemporal dementia (FTD) patients in comparison with healthy controls.
Analysis of eighteen PIN1 common polymorphisms and their haplotypes in EOAD, LOAD and FTD individuals in comparison with the control group did not reveal their contribution to disease risk.In six unrelated familial AD patients four novel PIN1 sequence variants were detected. c.58+64C>T substitution that was identified in three patients, was located in an alternative exon. In silico analysis suggested that this variant highly increases a potential affinity for a splicing factor and introduces two intronic splicing enhancers. In the peripheral leukocytes of one living patient carrying the variant, a 2.82 fold decrease in PIN1 expression was observed.
Our data does not support the role of PIN1 common polymorphisms as AD risk factor. However, we suggest that the identified rare sequence variants could be directly connected with AD pathology, influencing PIN1 splicing and/or expression.
肽基脯氨酰异构酶NIMA相互作用蛋白1（PIN1）在大脑中发挥重要作用，并参与许多与阿尔茨海默病（AD）和其他神经退行性疾病相关的细胞过程。关于AD大脑中PIN1活性的结果存在混淆。此外，PIN1基因变异与AD风险的关联也不一致。
我们对早发型和晚发型AD以及额颞叶痴呆（FTD）患者的PIN1编码区和启动子区进行了分析，并与健康对照进行比较。
与对照组相比，对早发型AD（EOAD）、晚发型AD（LOAD）和FTD个体中18种PIN1常见多态性及其单倍型的分析未发现它们对疾病风险有贡献。在6名无亲缘关系的家族性AD患者中检测到4种新的PIN1序列变异。在3名患者中鉴定出的c.58 + 64C>T替换位于一个可变外显子中。计算机分析表明，该变异显著增加了对剪接因子的潜在亲和力，并引入了两个内含子剪接增强子。在一名携带该变异的在世患者的外周血白细胞中，观察到PIN1表达下降了2.82倍。
我们的数据不支持PIN1常见多态性作为AD风险因素的作用。然而，我们认为所鉴定的罕见序列变异可能与AD病理直接相关，影响PIN1的剪接和/或表达。
