Rademakers Rosa, Baker Matt, Gass Jennifer, Adamson Jennifer, Huey Edward D, Momeni Parastoo, Spina Salvatore, Coppola Giovanni, Karydas Anna M, Stewart Heather, Johnson Nancy, Hsiung Ging-Yuek, Kelley Brendan, Kuntz Karen, Steinbart Ellen, Wood Elisabeth McCarty, Yu Chang-En, Josephs Keith, Sorenson Eric, Womack Kyle B, Weintraub Sandra, Pickering-Brown Stuart M, Schofield Peter R, Brooks William S, Van Deerlin Vivianna M, Snowden Julie, Clark Christopher M, Kertesz Andrew, Boylan Kevin, Ghetti Bernardino, Neary David, Schellenberg Gerard D, Beach Thomas G, Mesulam Marsel, Mann David, Grafman Jordan, Mackenzie Ian R, Feldman Howard, Bird Thomas, Petersen Ron, Knopman David, Boeve Bradley, Geschwind Dan H, Miller Bruce, Wszolek Zbigniew, Lippa Carol, Bigio Eileen H, Dickson Dennis, Graff-Radford Neill, Hutton Mike
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
Lancet Neurol. 2007 Oct;6(10):857-68. doi: 10.1016/S1474-4422(07)70221-1.
The progranulin gene (GRN) is mutated in 5-10% of patients with frontotemporal lobar degeneration (FTLD) and in about 20% of patients with familial FTLD. The most common mutation in GRN is Arg493X. We aimed to establish the contribution of this mutation to FTLD and related disorders.
We measured the frequency of Arg493X in 3405 unrelated patients with various neurodegenerative diseases using Taqman single-nucleotide polymorphism (SNP) genotyping. Clinicopathological characterisation and shared haplotype analysis were done for 30 families with FTLD who carry Arg493X. To investigate the effect of potential modifying loci, we did linear regression analyses with onset age as the covariate for GRN variants, for genotypes of the apolipoprotein E gene (APOE), and for haplotypes of the microtubule-associated protein tau gene (MAPT).
Of 731 patients with FTLD, 16 (2%) carried Arg493X. This mutation was not detected in 2674 patients who did not have FTLD. In 37 patients with Arg493X from 30 families with FTLD, clinical diagnoses included frontotemporal dementia, primary progressive aphasia, corticobasal syndrome, and Alzheimer's disease. Range of onset age was 44-69 years. In all patients who came to autopsy (n=13), the pathological diagnosis was FTLD with neuronal inclusions that contained TAR DNA-binding protein or ubiquitin, but not tau. Neurofibrillary tangle pathology in the form of Braak staging correlated with overall neuropathology in the Arg493X carriers. Haplotype analyses suggested that Arg493X arose twice, with a single founder for 27 families. Linear regression analyses suggested that patients with SNP rs9897528 on their wild-type GRN allele have delayed symptom onset. Onset ages were not associated with the MAPT H1 or H2 haplotypes or APOE genotypes, but early memory deficits were associated with the presence of an APOE epsilon4 allele.
Clinical heterogeneity is associated with GRN haploinsufficiency, and genetic variability on the wild-type GRN allele might have a role in the age-related disease penetrance of GRN mutations.
在5%-10%的额颞叶变性（FTLD）患者以及约20%的家族性FTLD患者中，颗粒蛋白前体基因（GRN）发生突变。GRN中最常见的突变是Arg493X。我们旨在确定该突变对FTLD及相关疾病的影响。
我们使用Taqman单核苷酸多态性（SNP）基因分型技术，检测了3405例患有各种神经退行性疾病的非亲属患者中Arg493X的频率。对30个携带Arg493X的FTLD家族进行了临床病理特征分析和共享单倍型分析。为了研究潜在修饰位点的作用，我们以发病年龄作为协变量，对GRN变异体、载脂蛋白E基因（APOE）的基因型以及微管相关蛋白tau基因（MAPT）的单倍型进行了线性回归分析。
在731例FTLD患者中，16例（2%）携带Arg493X。在2674例非FTLD患者中未检测到该突变。在来自30个FTLD家族的37例携带Arg493X的患者中，临床诊断包括额颞叶痴呆、原发性进行性失语、皮质基底节综合征和阿尔茨海默病。发病年龄范围为44-69岁。在所有进行尸检的患者（n=13）中，病理诊断为FTLD伴神经元包涵体，其中含有TAR DNA结合蛋白或泛素，但不含tau。以Braak分期形式存在的神经纤维缠结病理与Arg493X携带者的总体神经病理相关。单倍型分析表明，Arg493X出现了两次，27个家族有一个共同的起源。线性回归分析表明，野生型GRN等位基因上携带SNP rs9897528的患者症状发作延迟。发病年龄与MAPT H1或H2单倍型或APOE基因型无关，但早期记忆缺陷与APOE ε4等位基因的存在有关。
临床异质性与GRN单倍剂量不足相关，野生型GRN等位基因上的遗传变异性可能在GRN突变的年龄相关疾病外显率中起作用。
