Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members.
Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members.
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DOI：
10.1093/brain/awn352
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发表时间：
2009-03
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影响因子：
--
通讯作者：
Rademakers R
中科院分区：
文献类型：
--
作者：
Finch N;Baker M;Crook R;Swanson K;Kuntz K;Surtees R;Bisceglio G;Rovelet-Lecrux A;Boeve B;Petersen RC;Dickson DW;Younkin SG;Deramecourt V;Crook J;Graff-Radford NR;Rademakers R
颗粒体蛋白前体基因 (GRN) 突变是导致泛素和 TAR DNA 结合蛋白 43 (TDP43) 阳性病理学的额颞叶变性 (FTLD) 的重要原因。与 GRN 突变相关的临床表现是异质的，可能包括临床上可能的阿尔茨海默病。迄今为止发现的所有 GRN 突变均通过统一的疾病机制引起疾病，即功能性 GRN 的丧失或单倍体不足。为了确定血浆中 GRN 的表达是否可以预测 GRN 突变状态并可用作生物标志物，我们优化了 GRN ELISA，并研究了连续临床 FTLD 系列的血浆样本，其中包括 219 名患者、70 名对照个体、72 名早发的可能阿尔茨海默病患者以及 9 名有症状和 18 名 GRN 突变家族亲属的无症状亲属。所有携带 GRN 功能丧失突变的 FTLD 患者血浆中 GRN 水平显着降低，约为非 GRN 携带者和对照个体中观察到的水平的三分之一 (P < 0.001)。在 8 名 GRN 功能丧失突变携带者（范围：53-94 ng/ml）和 191 名非 GRN 突变携带者（范围：115-386 ng/ml）之间没有观察到 GRN 水平分布重叠。在无症状 GRN 突变携带者中也发现了类似的低水平 GRN。重要的是，ELISA 分析还发现一名可能的阿尔茨海默病患者 (1.4%) 携带 GRN 功能丧失突变。生化分析进一步表明，GRN ELISA 只能检测全长 GRN，不能检测中间颗粒蛋白片段。这项研究表明，使用血浆中的 GRN ELISA，可以准确检测有症状和无症状携带者的致病性 GRN 突变。全长 GRN 减少约 75%，表明功能丧失突变携带者的 GRN 代谢不平衡，从而更多的 GRN 被加工成颗粒蛋白。我们建议血浆 GRN 水平可以作为一种可靠且廉价的工具来识别早发性痴呆人群和无症状高危个体中的所有 GRN 突变携带者。
Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD) with ubiquitin and TAR DNA-binding protein 43 (TDP43)-positive pathology. The clinical presentation associated with GRN mutations is heterogeneous and may include clinical probable Alzheimer's disease. All GRN mutations identified thus far cause disease through a uniform disease mechanism, i.e. the loss of functional GRN or haploinsufficiency. To determine if expression of GRN in plasma could predict GRN mutation status and could be used as a biological marker, we optimized a GRN ELISA and studied plasma samples of a consecutive clinical FTLD series of 219 patients, 70 control individuals, 72 early-onset probable Alzheimer's disease patients and nine symptomatic and 18 asymptomatic relatives of GRN mutation families. All FTLD patients with GRN loss-of-function mutations showed significantly reduced levels of GRN in plasma to about one third of the levels observed in non-GRN carriers and control individuals (P < 0.001). No overlap in distributions of GRN levels was observed between the eight GRN loss-of-function mutation carriers (range: 53–94 ng/ml) and 191 non-GRN mutation carriers (range: 115–386 ng/ml). Similar low levels of GRN were identified in asymptomatic GRN mutation carriers. Importantly, ELISA analyses also identified one probable Alzheimer's disease patient (1.4%) carrying a loss-of-function mutation in GRN. Biochemical analyses further showed that the GRN ELISA only detects full-length GRN, no intermediate granulin fragments. This study demonstrates that using a GRN ELISA in plasma, pathogenic GRN mutations can be accurately detected in symptomatic and asymptomatic carriers. The ∼75% reduction in full-length GRN, suggests an unbalanced GRN metabolism in loss-of-function mutation carriers whereby more GRN is processed into granulins. We propose that plasma GRN levels could be used as a reliable and inexpensive tool to identify all GRN mutation carriers in early-onset dementia populations and asymptomatic at-risk individuals.
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影响因子：
64.8
作者：
Cruts, Marc;Gijselinck, Ilse;Van Broeckhoven, Christine
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