Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6.

Abstract

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.

• Authors: Caroline Vance, Boris Rogelj, Tibor Hortobágyi, Kurt J De Vos, Agnes Lumi Nishimura, Jemeen Sreedharan, Xun Hu, Bradley Smith, Deborah Ruddy, Paul Wright, Jeban Ganesalingam, Kelly L Williams, Vineeta Tripathi, Safa Al-Saraj, Ammar Al-Chalabi, P Nigel Leigh, Ian P Blair, Garth Nicholson, Jackie de Belleroche, Jean-Marc Gallo, Christopher C Miller, Christopher E Shaw
• Journal: Science (New York, N.Y.) (Science) Vol. 323 Issue 5918 Pg. 1208-1211 (Feb 27 2009) ISSN: 1095-9203 [Electronic] United States
• PMID: 19251628 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• RNA-Binding Protein FUS

Topics

• Age of Onset
• Amino Acid Sequence
• Amyotrophic Lateral Sclerosis (genetics, metabolism, pathology)
• Animals
• Brain (pathology)
• Cell Line
• Cell Nucleus (metabolism)
• Cytoplasm (metabolism)
• DNA-Binding Proteins (analysis, genetics, metabolism)
• Female
• Humans
• Inclusion Bodies (chemistry, ultrastructure)
• Male
• Molecular Sequence Data
• Motor Neurons (metabolism)
• Mutation, Missense
• Pedigree
• RNA-Binding Protein FUS (analysis, genetics, metabolism)
• Rats
• Spinal Cord (pathology)
• Transfection