Serum Progranulin Levels in Patients with Frontotemporal Lobar Degeneration and Alzheimer's Disease: Detection of GRN Mutations in a Spanish Cohort
Serum Progranulin Levels in Patients with Frontotemporal Lobar Degeneration and Alzheimer's Disease: Detection of GRN Mutations in a Spanish Cohort
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DOI：
10.3233/jad-2012-112120
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发表时间：
2012-01-01
影响因子：
4
通讯作者：
Llado, Albert
中科院分区：
文献类型：
--
作者：
Antonell, Anna;Gil, Silvia;Llado, Albert
颗粒蛋白前体基因（GRN）突变引起具有TDP 43阳性包涵体的额颞叶变性（FTLD），尽管其临床表型是异质性的，并且包括分类为行为变体-FTLD（bvFTLD）、进行性非流畅性失语（PNFA）、皮质基底综合征、阿尔茨海默病（AD）或帕金森病（PD）的患者。我们的主要目的是研究在西班牙FTLD或AD患者队列中，低血清颗粒蛋白前体蛋白（PGRN）水平是否可以检测到GRN突变。在112名受试者中测量血清PGRN水平：17名bvFTLD，20名PNFA，4名语义性痴呆，34名散发性AD，9名AD-PSEN 1突变携带者，10名症状前PSEN 1突变携带者和18名对照个体。我们检测到5例PGRN水平低于94 ng/mL的患者：其中2例临床诊断为bvFTLD，2例为PNFA，1例为AD。GRN突变筛查在3例患者中检测到2个可能的致病突变（p.C366fsX1和一个新突变：p.V279GfsX5），在1例患者中检测到1个致病性质不明的突变（p.C139R）。另一名患者显示正常的GRN序列，但携带PRNP基因突变。我们观察到对照组（平均值= 145.5 ng/mL，SD = 28.5）和其他神经退行性疾病之间血清PGRN水平无差异，病理性GRN基因突变携带者除外（平均值= 50.5 ng/mL，SD = 21.2）。PRNP突变携带者的血清PGRN水平也低于p.C139R携带者（92.3 ng/mL）和PRNP突变携带者（76.9 ng/mL）。总之，我们在血清PGRN水平严重降低的患者中检测到GRN无效突变，但在PGRN水平轻微降低的患者中未检测到。
Progranulin gene (GRN) mutations cause frontotemporal lobar degeneration (FTLD) with TDP43-positive inclusions, although its clinical phenotype is heterogeneous and includes patients classified as behavioral variant-FTLD (bvFTLD), progressive non-fluent aphasia (PNFA), corticobasal syndrome, Alzheimer's disease (AD), or Parkinson's disease (PD). Our main objective was to study if low serum progranulin protein (PGRN) levels may detect GRN mutations in a Spanish cohort of patients with FTLD or AD. Serum PGRN levels were measured in 112 subjects: 17 bvFTLD, 20 PNFA, 4 semantic dementia, 34 sporadic AD, 9 AD-PSEN1 mutation carriers, 10 presymptomatic-PSEN1 mutation carriers, and 18 control individuals. We detected 5 patients with PGRN levels below 94 ng/mL: two of them had a clinical diagnosis of bvFTLD, two of PNFA, and one of AD. The screening for GRN mutations detected two probable pathogenic mutations (p.C366fsX1 and a new mutation: p.V279GfsX5) in three patients and one mutation of unclear pathogenic nature (p.C139R) in one patient. The other patient showed a normal GRN sequence but carried a PRNP gene mutation. We observed no differences in serum PGRN levels between controls (mean = 145.5 ng/mL, SD = 28.5) and the other neurodegenerative diseases, except for the carriers of pathological GRN gene mutations (mean = 50.5 ng/mL, SD = 21.2). Null GRN mutation carriers also showed lower serum PGRN levels than the patient who was a carrier of p.C139R (92.3 ng/mL) and the one who was a carrier of the PRNP mutation (76.9 ng/mL). In conclusion, we detected GRN null mutations in patients with severely reduced serum PGRN levels, but not in patients with slightly reduced PGRN levels.