Striking phenotypic variation in a family with the P506S UBQLN2 mutation including amyotrophic lateral sclerosis, spastic paraplegia, and frontotemporal dementia.
Striking phenotypic variation in a family with the P506S UBQLN2 mutation including amyotrophic lateral sclerosis, spastic paraplegia, and frontotemporal dementia.
复制标题
P506S UBQLN2 突变家族的显着表型变异包括肌萎缩侧索硬化症、痉挛性截瘫和额颞叶痴呆。
DOI：
10.1016/j.neurobiolaging.2018.08.015
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发表时间：
2019
影响因子：
4.2
通讯作者：
Gkazi SA
中科院分区：
文献类型：
--
作者：
Gkazi SA
对226例英国家族性肌萎缩侧索硬化症（ALS）和额颞叶痴呆患者的外显子组测序分析发现，2例患者分别携带P497H和p506subqln2突变（n = 0.9%）。P506S指数病例在54岁时表现为行为变异性额颞叶痴呆，并在存活3年后发展为ALS。三个儿子分别表现为：(1)25岁发病的缓慢进行性纯痉挛性截瘫；(2)发病25年、生存2年的ALS；(3) 26岁出现症状的ALS。对指标病例的死后组织进行分析，发现齿状回中频繁出现ubqln2阳性神经元胞质包裹体，海马齿状回额叶皮层、颞叶皮层和颗粒细胞层中频繁出现tdp -43阳性神经元胞质包裹体。此外，对已发表的dubqln2突变的综合分析表明，只有脯氨酸丰富结构域突变导致男性患者发病年龄显著提前（p= 0.0026）。
Analysis of 226 exome-sequenced UK cases of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia identified 2 individuals who harbored a P497H and P506SUBQLN2mutation, respectively (n = 0.9%). The P506S index case presented with behavioral variant frontotemporal dementia at the age of 54 years then progressed to ALS surviving 3 years. Three sons presented with (1) slowly progressive pure spastic paraplegia with an onset at 25 years and (2) ALS with disease onset of 25 years and survival of 2 years, and (3) ALS presenting symptoms at the age of 26 years, respectively. Analysis of postmortem tissue from the index case revealed frequent neuronal cytoplasmic UBQLN2-positive inclusions in the dentate gyrus and TDP-43-positive neuronal cytoplasmic inclusions in the frontal and temporal cortex and granular cell layer of the dentate gyrus of the hippocampus. Furthermore, a comprehensive analysis of publishedUBQLN2mutations demonstrated that only proline-rich domain mutations contribute to a significantly earlier age of onset in male patients (p= 0.0026).