Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6.
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.
Vance
Caroline
C
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
Rogelj
Boris
B
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
Hortobágyi
Tibor
T
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
De Vos
Kurt J
KJ
Department of Neuroscience, King's College London, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
Nishimura
Agnes Lumi
AL
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
Sreedharan
Jemeen
J
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
Hu
Xun
X
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
Smith
Bradley
B
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
Ruddy
Deborah
D
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
Wright
Paul
P
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
Ganesalingam
Jeban
J
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
Williams
Kelly L
KL
Northcott Neuroscience Laboratory, Australian and New Zealand Army Corps (ANZAC) Research Institute, Concord, NSW 2139, Australia.
Tripathi
Vineeta
V
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
Al-Saraj
Safa
S
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
Al-Chalabi
Ammar
A
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
Leigh
P Nigel
PN
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
Blair
Ian P
IP
Northcott Neuroscience Laboratory, Australian and New Zealand Army Corps (ANZAC) Research Institute, Concord, NSW 2139, Australia.|Faculty of Medicine, University of Sydney, Sydney, NSW 2139, Australia.
Nicholson
Garth
G
Northcott Neuroscience Laboratory, Australian and New Zealand Army Corps (ANZAC) Research Institute, Concord, NSW 2139, Australia.|Molecular Medicine Laboratory, Concord Hospital, Concord, NSW 2139, Australia.|Faculty of Medicine, University of Sydney, Sydney, NSW 2139, Australia.
de Belleroche
Jackie
J
Division of Neurosciences and Mental Health, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.
Gallo
Jean-Marc
JM
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
Miller
Christopher C
CC
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.
Shaw
Christopher E
CE
Department of Clinical Neuroscience, King's College London, Medical Research Council (MRC) Centre for Neurodegeneration Research, Institute of Psychiatry, London SE5 8AF, UK.
D017668:Age of Onset; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000473:pathology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000737:chemistry / Q000648:ultrastructure; D008297:Male; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000378:metabolism; D020125:Mutation, Missense; D010375:Pedigree; D034702:RNA-Binding Protein FUS / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D013116:Spinal Cord / Q000473:pathology; D014162:Transfection
D004268:DNA-Binding Proteins; D034702:RNA-Binding Protein FUS