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Science 27 February 2009:
Vol. 323. no. 5918, pp. 1208 - 1211
DOI: 10.1126/science.1165942
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Reports

Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6

Caroline Vance,1* Boris Rogelj,1* Tibor Hortobágyi,1* Kurt J. De Vos,2* Agnes Lumi Nishimura,1 Jemeen Sreedharan,1 Xun Hu,1 Bradley Smith,1 Deborah Ruddy,1 Paul Wright,1 Jeban Ganesalingam,1 Kelly L. Williams,3 Vineeta Tripathi,1 Safa Al-Saraj,1 Ammar Al-Chalabi,1 P. Nigel Leigh,1 Ian P. Blair,3,5 Garth Nicholson,3,4,5 Jackie de Belleroche,6 Jean-Marc Gallo,1 Christopher C. Miller,1,2 Christopher E. Shaw1{dagger}

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.

1 Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
2 Department of Neuroscience, King's College London, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
3 Northcott Neuroscience Laboratory, Australian and New Zealand Army Corps (ANZAC) Research Institute, Concord, NSW 2139, Australia.
4 Molecular Medicine Laboratory, Concord Hospital, Concord, NSW 2139, Australia.
5 Faculty of Medicine, University of Sydney, Sydney, NSW 2139, Australia.
6 Division of Neurosciences and Mental Health, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: chris.shaw{at}iop.kcl.ac.uk

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