Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation
Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation
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DOI：
10.1007/s00401-009-0621-1
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发表时间：
2010-03-01
影响因子：
12.7
通讯作者：
Kira, Jun-ichi
中科院分区：
文献类型：
--
作者：
Tateishi, Takahisa;Hokonohara, Toshihiro;Kira, Jun-ichi
最近在家族性肌萎缩侧索硬化症（ALS）患者中发现了肉瘤融合基因（FUS）的突变。本研究旨在阐明日本人群中FUS突变引起的家族性ALS的独特特征。我们进行了临床，神经病理学和遗传学研究的一个大的日本家系与家族性ALS。在这个家族的连续六代中，16个个体的男性和女性都受到进行性肌肉萎缩和无力的影响，这表明了一种常染色体显性性状。6例患者的神经系统检查显示，第四代患者的发病年龄为48.2 +/- A 8.1岁，而第五代和第六代患者的发病年龄分别为31岁和20岁。这些患者的运动麻痹进展迅速，在1年内达到呼吸衰竭的高潮。4例患者FUS基因第15外显子存在错义突变c.1561C> T（p.R521C）。对一例FUS突变尸检病例的神经病理学研究显示，除了上、下运动神经元受累外，还有多系统变性：苍白球、丘脑、黑质、小脑、下橄榄核、孤核、中间外侧角、Clarke氏柱、Onuf氏核、中央被盖束、内侧丘系、内侧纵束、上级小脑脚、后柱、脊髓小脑束均退变。嗜银和嗜碱性神经元或胶质细胞胞质包涵体FUS，GRP 78/BiP，p62和泛素免疫反应检测受影响的病变。该日本家族的FUS R521 C突变导致家族性ALS，其病理特征为多系统变性和神经元嗜碱性包涵体。
Mutations in the fused in sarcoma gene (FUS) were recently found in patients with familial amyotrophic lateral sclerosis (ALS). The present study aimed to clarify unique features of familial ALS caused by FUS mutation in the Japanese population. We carried out clinical, neuropathological, and genetic studies on a large Japanese pedigree with familial ALS. In six successive generations of this family, 16 individuals of both sexes were affected by progressive muscle atrophy and weakness, indicating an autosomal dominant trait. Neurological examination of six patients revealed an age at onset of 48.2 +/- A 8.1 years in fourth generation patients, while it was 31 and 20 years in fifth and sixth generation patients, respectively. Motor paralysis progressed rapidly in these patients, culminating in respiratory failure within 1 year. The missense mutation c.1561 C > T (p.R521C) was found in exon 15 of FUS in the four patients examined. Neuropathological study of one autopsied case with the FUS mutation revealed multiple system degeneration in addition to upper and lower motor neuron involvement: the globus pallidus, thalamus, substantia nigra, cerebellum, inferior olivary nucleus, solitary nucleus, intermediolateral horn, Clarke's column, Onuf's nucleus, central tegmental tract, medial lemniscus, medial longitudinal fasciculus, superior cerebellar peduncle, posterior column, and spinocerebellar tract were all degenerated. Argyrophilic and basophilic neuronal or glial cytoplasmic inclusions immunoreactive for FUS, GRP78/BiP, p62, and ubiquitin were detected in affected lesions. The FUS R521C mutation in this Japanese family caused familial ALS with pathological features of multiple system degeneration and neuronal basophilic inclusions.