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

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

doi:10.1126/science.1165942

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

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 GalloChristopher C Miller, Christopher E Shaw

Research output: Contribution to journal › Article › peer-review

2145 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1208-11
Number of pages	4
Journal	Science
Volume	323
Issue number	5918
DOIs	https://doi.org/10.1126/science.1165942
Publication status	Published - 27 Feb 2009

Keywords

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

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Vance, C., Rogelj, B., Hortobágyi, T., De Vos, K. J., Nishimura, A. L., Sreedharan, J., Hu, X., Smith, B., Ruddy, D., Wright, P., Ganesalingam, J., Williams, K. L., Tripathi, V., Al-Saraj, S., Al-Chalabi, A., Leigh, P. N., Blair, I. P., Nicholson, G., de Belleroche, J., ... Shaw, C. E. (2009). Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science, 323(5918), 1208-11. https://doi.org/10.1126/science.1165942

@article{eac6446c223b4b97842051ba7ab52df9,

title = "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.",

keywords = "Pedigree, Animals, Spinal Cord, Age of Onset, DNA-Binding Proteins, Humans, Inclusion Bodies, Brain, Amino Acid Sequence, Cell Nucleus, Mutation, Missense, Rats, Transfection, Amyotrophic Lateral Sclerosis, RNA-Binding Protein FUS, Cytoplasm, Molecular Sequence Data, Cell Line, Female, Male, Motor Neurons",

author = "Caroline Vance and Boris Rogelj and Tibor Hortob{\'a}gyi and {De Vos}, {Kurt J} and Nishimura, {Agnes Lumi} and Jemeen Sreedharan and Xun Hu and Bradley Smith and Deborah Ruddy and Paul Wright and Jeban Ganesalingam and Williams, {Kelly L} and Vineeta Tripathi and Safa Al-Saraj and Ammar Al-Chalabi and Leigh, {P Nigel} and Blair, {Ian P} and Garth Nicholson and {de Belleroche}, Jackie and Jean-Marc Gallo and Miller, {Christopher C} and Shaw, {Christopher E}",

year = "2009",

month = feb,

day = "27",

doi = "10.1126/science.1165942",

language = "English",

volume = "323",

pages = "1208--11",

journal = "Science",

issn = "1095-9203",

publisher = "American Association for the Advancement of Science",

number = "5918",

}

Vance, C , Rogelj, B , Hortobágyi, T , De Vos, KJ , Nishimura, AL , Sreedharan, J , Hu, X , Smith, B , Ruddy, D , Wright, P , Ganesalingam, J, Williams, KL, Tripathi, V, Al-Saraj, S, Al-Chalabi, A , Leigh, PN, Blair, IP, Nicholson, G, de Belleroche, J, Gallo, J-M , Miller, CC & Shaw, CE 2009, 'Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6', Science, vol. 323, no. 5918, pp. 1208-11. https://doi.org/10.1126/science.1165942

TY - JOUR

T1 - Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6

AU - Vance, Caroline

AU - Rogelj, Boris

AU - Hortobágyi, Tibor

AU - De Vos, Kurt J

AU - Nishimura, Agnes Lumi

AU - Sreedharan, Jemeen

AU - Hu, Xun

AU - Smith, Bradley

AU - Ruddy, Deborah

AU - Wright, Paul

AU - Ganesalingam, Jeban

AU - Williams, Kelly L

AU - Tripathi, Vineeta

AU - Al-Saraj, Safa

AU - Al-Chalabi, Ammar

AU - Leigh, P Nigel

AU - Blair, Ian P

AU - Nicholson, Garth

AU - de Belleroche, Jackie

AU - Gallo, Jean-Marc

AU - Miller, Christopher C

AU - Shaw, Christopher E

PY - 2009/2/27

Y1 - 2009/2/27

N2 - 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.

AB - 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.

KW - Pedigree

KW - Animals

KW - Spinal Cord

KW - Age of Onset

KW - DNA-Binding Proteins

KW - Humans

KW - Inclusion Bodies

KW - Brain

KW - Amino Acid Sequence

KW - Cell Nucleus

KW - Mutation, Missense

KW - Rats

KW - Transfection

KW - Amyotrophic Lateral Sclerosis

KW - RNA-Binding Protein FUS

KW - Cytoplasm

KW - Molecular Sequence Data

KW - Cell Line

KW - Female

KW - Male

KW - Motor Neurons

U2 - 10.1126/science.1165942

DO - 10.1126/science.1165942

M3 - Article

C2 - 19251628

SN - 1095-9203

VL - 323

SP - 1208

EP - 1211

JO - Science

JF - Science

IS - 5918

ER -

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

Abstract

Keywords

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