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 m...

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Published in:	Science (American Association for the Advancement of Science) 2009-02, Vol.323 (5918), p.1208-1211
Main Authors:	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
Format:	Article
Language:	eng
Subjects:	Age of Onset Amino Acid Sequence Amyotrophic lateral sclerosis Amyotrophic Lateral Sclerosis - genetics Amyotrophic Lateral Sclerosis - metabolism Amyotrophic Lateral Sclerosis - pathology Animals Biological and medical sciences Brain - pathology Cell Line Cell lines Cell Nucleus - metabolism Cerebrospinal fluid. Meninges. Spinal cord Cytoplasm - metabolism Cytoplasmic inclusions Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases DNA-Binding Proteins - analysis DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Families & family life Female Genetic mutation Genetics Humans Inclusion Bodies - chemistry Inclusion Bodies - ultrastructure Male Medical research Medical sciences Molecular Sequence Data Motor neurons Motor Neurons - metabolism Mutation Mutation, Missense Nervous system (semeiology, syndromes) Nervous system diseases Neurodegenerative diseases Neurology Neurons Pedigree Proteins Rats RNA-Binding Protein FUS - analysis RNA-Binding Protein FUS - genetics RNA-Binding Protein FUS - metabolism Spinal Cord - pathology Transfection
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Summary:	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.
ISSN:	0036-8075 1095-9203