Vance Caroline, Rogelj Boris, Hortobágyi Tibor, De Vos Kurt J, Nishimura Agnes Lumi, Sreedharan Jemeen, Hu Xun, Smith Bradley, Ruddy Deborah, Wright Paul, Ganesalingam Jeban, Williams Kelly L, Tripathi Vineeta, Al-Saraj Safa, Al-Chalabi Ammar, Leigh P Nigel, Blair Ian P, Nicholson Garth, de Belleroche Jackie, Gallo Jean-Marc, Miller Christopher C, Shaw Christopher E
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
Department of Neuroscience, King's College London, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
Science. 2009 Feb 27;323(5918):1208-1211. doi: 10.1126/science.1165942.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is familial in 10% of cases. We have identified a missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6. In a survey of 197 familial ALS index cases, we identified two further missense mutations in eight families. Postmortem analysis of three cases with FUS mutations showed FUS-immunoreactive cytoplasmic inclusions and predominantly lower motor neuron degeneration. Cellular expression studies revealed aberrant localization of mutant FUS protein. FUS is involved in the regulation of transcription and RNA splicing and transport, and it has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，10%的病例为家族性。我们在一个与ALS6相关的英国家族中，发现了编码肉瘤融合蛋白（FUS）的基因中的一个错义突变。在对197个家族性ALS索引病例的调查中，我们在8个家族中又发现了另外两个错义突变。对3例FUS突变病例的尸检分析显示，有FUS免疫反应性胞质包涵体，且主要是下运动神经元变性。细胞表达研究揭示了突变FUS蛋白的异常定位。FUS参与转录、RNA剪接和转运的调控，并且它与另一个ALS基因TARDBP具有功能同源性，这表明运动神经元变性可能存在共同机制。
