The unexpected co-occurrence of <i>GRN</i> and <i>MAPT</i> p.A152T in Basque families: Clinical and pathological characteristics

Background The co-occurrence of the c.709-1G>A GRN mutation and the p.A152T MAPT variant has been identified in 18 Basque families affected by frontotemporal dementia (FTD). We aimed to investigate the influence of the p.A152T MAPT variant on the clinical and neuropathological features of these Basque GRN families. Methods and findings We compared clinical characteristics of 14 patients who carried the c.709-1G>A GRN mutation (GRN+/A152T-) with 21 patients who carried both the c.709-1G>A GRN mutation and the p.A152T MAPT variant (GRN+/A152T+). Neuropsychological data (n = 17) and plasma progranulin levels (n = 23) were compared between groups, and 7 subjects underwent neuropathological studies. We genotyped six short tandem repeat markers in the two largest families. By the analysis of linkage disequilibrium decay in the haplotype block we estimated the time when the first ancestor to carry both genetic variants emerged. GRN+/A152T+ and GRN+/A152T- patients shared similar clinical and neuropsychological features and plasma progranulin levels. All were diagnosed with an FTD disorder, including behavioral variant FTD or non fluent / agrammatic variant primary progressive aphasia, and shared a similar pattern of neuropsychological deficits, predominantly in executive function, memory, and language. All seven participants with available brain autopsies (6 GRN+/A152T+, 1 GRN+/A152T-) showed frontotemporal lobar degeneration with TDP-43 inclusions (type A classification), which is characteristic of GRN carriers. Additionally, all seven showed mild to moderate tau inclusion burden: five cases lacked β-amyloid pathology and two cases had Alzheimer’s pathology. The co-occurrence of both genes within one individual is recent, with the birth of the first GRN+/A152T+ individual estimated to be within the last 50 generations (95% probability). Conclusions In our sample, the p.A152T MAPT variant does not appear to show a discernible influence on the clinical phenotype of GRN carriers. Whether p.A152T confers a greater than expected propensity for tau pathology in these GRN carriers remains an open question.### 研究背景 本研究在18个受额颞叶痴呆（frontotemporal dementia, FTD）影响的巴斯克家族中，发现了c.709-1G>A GRN基因突变与p.A152T MAPT变异体共存的现象。本研究旨在探究p.A152T MAPT变异体对这些巴斯克GRN家族患者的临床及神经病理特征的影响。 ### 研究方法与结果 本研究比较了两组患者的临床特征：14名仅携带c.709-1G>A GRN基因突变的患者（GRN+/A152T-），以及21名同时携带c.709-1G>A GRN基因突变与p.A152T MAPT变异体的患者（GRN+/A152T+）。研究还比较了两组的神经心理学数据（n=17）与血浆颗粒蛋白前体（progranulin）水平（n=23），并对7名受试者进行了神经病理学研究。我们对两个最大家族中的6个短串联重复序列（short tandem repeat, STR）标记进行了基因分型。通过分析单倍型区块内的连锁不平衡衰减情况，我们估算出同时携带这两种遗传变异的共同祖先出现的时间。 结果显示，GRN+/A152T+与GRN+/A152T-患者的临床特征、神经心理学表现及血浆颗粒蛋白前体水平均相似。所有患者均被诊断为额颞叶痴呆，包括行为变异型额颞叶痴呆或非流利/语法缺失型原发性进行性失语（primary progressive aphasia, PPA），且神经心理学缺陷模式相似，主要累及执行功能、记忆与语言领域。7名具备脑尸检数据的受试者（6名为GRN+/A152T+，1名为GRN+/A152T-）均表现为伴TDP-43（transactive response DNA-binding protein 43）包涵体的额颞叶变性（A型分类），这是GRN突变携带者的典型病理特征。此外，7名受试者均存在轻至中度的tau包涵体负荷：其中5例无β-淀粉样蛋白病理改变，2例合并阿尔茨海默病病理改变。两种基因在同一人体内共存的事件发生较晚，首次出现GRN+/A152T+个体的时间估计在过去50代以内（95%置信概率）。 ### 研究结论 在本研究队列中，p.A152T MAPT变异体似乎并未对GRN突变携带者的临床表型产生可识别的影响。p.A152T是否会使这些GRN突变携带者出现tau病理的倾向高于预期，仍是一个尚未明确的科学问题。