Almeida Maria Rosário, Baldeiras Inês, Ribeiro Maria Helena, Santiago Beatriz, Machado Cristina, Massano João, Guimarães Joana, Resende Oliveira Catarina, Santana Isabel
CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Neurodegener Dis. 2014;13(4):214-23. doi: 10.1159/000352022. Epub 2013 Sep 6.
Progranulin (PGRN) mutations are associated with different clinical phenotypes, including frontotemporal lobar degeneration (FTLD), corticobasal syndrome (CBS) and Alzheimer's disease (AD). As all pathogenic PGRN mutations identified so far cause disease through haploinsufficiency, determination of PGRN levels has been proposed as a reliable method to identify mutation carriers.
To evaluate the accuracy of peripheral PGRN levels in the identification of the PGRN mutation carriers detected thus far in our Portuguese cohort.
Serum PGRN levels were measured in 244 subjects (124 patients in the spectrum of FTLD, 2 asymptomatic descendants of a FTLD patient, 56 AD patients and 64 controls) by a novel commercial ELISA kit.
Low PGRN levels were detected in 7 individuals (5 behavioral variant frontotemporal dementia, 1 CBS, and 1 still clinically unaffected) that constituted the group of the null PGRN mutation carriers previously identified in our molecular diagnostic laboratory. The pathogenic mutations found consisted of 4 insertion-deletions, causing frameshifts resulting in premature stop codons, 3 of which were novel. In addition, a normal PGRN level was found in a patient harboring a novel missense variant. For this novel ELISA kit, we established a PGRN cut-off level that identified with 100% accuracy the pathogenic mutation carriers.
This study supports the use of a novel assay for the determination of PGRN levels as a screening procedure to identify patients harboring null PGRN mutations. This approach would significantly decrease the required PGRN mutation analysis workload and should be extended to other clinical phenotypes than behavioral variant frontotemporal dementia and to apparently sporadic cases.
颗粒蛋白前体（PGRN）突变与不同的临床表型相关，包括额颞叶变性（FTLD）、皮质基底节综合征（CBS）和阿尔茨海默病（AD）。由于迄今鉴定出的所有致病性PGRN突变均通过单倍剂量不足导致疾病，因此测定PGRN水平被提议作为识别突变携带者的可靠方法。
评估外周血PGRN水平在识别我们葡萄牙队列中迄今检测到的PGRN突变携带者方面的准确性。
使用一种新型商业ELISA试剂盒测定了244名受试者（124例FTLD谱系患者、2例FTLD患者的无症状后代、56例AD患者和64名对照）的血清PGRN水平。
在7名个体中检测到低PGRN水平（5例行为变异型额颞叶痴呆、1例CBS和1例仍无临床症状），这些个体构成了我们分子诊断实验室先前鉴定的无PGRN突变携带者组。发现的致病突变包括4个插入缺失，导致移码并产生过早终止密码子，其中3个是新发现的。此外，在一名携带新型错义变异的患者中发现PGRN水平正常。对于这种新型ELISA试剂盒，我们确定了一个PGRN临界值水平，该水平能100%准确识别致病突变携带者。
本研究支持使用一种新型检测方法测定PGRN水平作为一种筛查程序，以识别携带无PGRN突变的患者。这种方法将显著减少所需的PGRN突变分析工作量，并且应扩展到行为变异型额颞叶痴呆以外的其他临床表型以及明显散发的病例。
