Novel exon 1 progranulin gene variant in Alzheimer's disease
Novel exon 1 progranulin gene variant in Alzheimer's disease
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DOI：
10.1111/j.1468-1331.2008.02266.x
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发表时间：
2008-10-01
影响因子：
5.1
通讯作者：
Galimberti, D.
中科院分区：
文献类型：
--
作者：
Cortini, F.;Fenoglio, C.;Galimberti, D.
背景和目的：颗粒蛋白前体（PGRN）的表达在阿尔茨海默病（AD）脑中的活化小胶质细胞中增加，表明在这种病理学中的潜在作用。研究方法：对120例散发性额颞叶变性患者和145例散发性AD患者进行了PGRN外显子和侧翼区突变扫描。结果：在尚未保藏的变异体中，在外显子1（g100169 G> A）中鉴定出新的等位基因变异体。它导致氨基酸变化（p.Gly35Arg），并在迟发性AD患者中观察到。计算机模拟分析预测，这种突变可能是有害的。第二个变异（g.100165C > T），导致沉默突变（pAsp 33 Asp），被发现在语义性痴呆患者和另一个早发性AD。在226个对照中，两种变体均不存在。此外，观察到两种非常接近PGRN剪接位点区域的罕见非致病性变体（IVS 2 + 7 -> G > A和IVS 7 + 7 -> G > A）。患者外周血单核细胞的转录分析表明，它们不影响外显子剪接。结论：一个新的推定PGRN突变导致氨基酸取代被确定在临床AD患者。
Background and purpose: Progranulin (PGRN) expression is increased in activated microglia in Alzheimer's disease (AD) brain, suggesting a potential role in this pathology. Methods: A mutation scanning of exons and flanking regions of PGRN was carried out in 120 patients with sporadic frontotemporal lobar degeneration and 145 with sporadic AD. Results: Amongst variants not yet deposited, a novel allelic variant was identified in Exon 1 (g100169G > A). It leads to an amino acidic change (p.Gly35Arg) and was observed in a patient with late onset AD. In silico analysis predicted that this mutation is possibly damaging. A second variant (g.100165C > T), resulting in a silent mutation (pAsp33Asp), was found in a patient with semantic dementia and in another with early onset AD. Both variants were absent in 226 controls. In addition, two rare non-pathogenic variants lying very close to PGRN splice-site regions (IVS2 + 7 -> G > A and IVS7 + 7 -> G > A) were observed. Transcriptional analysis in peripheral blood mononuclear cells from patients demonstrated they do not affect exon splicing. Conclusions: A novel putative PGRN mutation leading to an amino acidic substitution was identified in a patient with clinical AD.