Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Mutations in the FUS/TLS Gene on Chromosome 16 Cause Familial Amyotrophic Lateral Sclerosis
T. J. Kwiatkowski, Jr.,1*D. A. Bosco,1,2A. L. LeClerc,1,2E. Tamrazian,1C. R. Vanderburg,3C. Russ,1,4A. Davis,1J. Gilchrist,5E. J. Kasarskis,6T. Munsat,7P. Valdmanis,8G. A. Rouleau,8B. A. Hosler,1P. Cortelli,9P. J. de Jong,10Y. Yoshinaga,10J. L. Haines,11M. A. Pericak-Vance,12J. Yan,13N. Ticozzi,1,2,14T. Siddique,13D. McKenna-Yasek,1P. C. Sapp,1,15H. R. Horvitz,15J. E. Landers,1,2R. H. Brown, Jr.1,2*
Amyotrophic lateral sclerosis (ALS) is a fatal degenerativemotor neuron disorder. Ten percent of cases are inherited; mostinvolve unidentified genes. We report here 13 mutations in thefused in sarcoma/translated in liposarcoma (FUS/TLS) gene onchromosome 16 that were specific for familial ALS. The FUS/TLSprotein binds to RNA, functions in diverse processes, and isnormally located predominantly in the nucleus. In contrast,the mutant forms of FUS/TLS accumulated in the cytoplasm ofneurons, a pathology that is similar to that of the gene TARDNA-binding protein 43 (TDP43), whose mutations also cause ALS.Neuronal cytoplasmic protein aggregation and defective RNA metabolismthus appear to be common pathogenic mechanisms involved in ALSand possibly in other neurodegenerative disorders.
1 Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA. 2 Department of Neurology, University of Massachusetts School of Medicine, Worcester, MA 01655, USA. 3 Massachusetts General Institute for Neurodegeneration, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA. 4 Broad Institute, Massachusetts Institute of Technology (MIT), Cambridge, MA 02141, USA. 5 Department of Neurology, Rhode Island Hospital, Providence, RI 02192, USA. 6 Department of Neurology, Veterans Affairs Medical Center, University of Kentucky, Lexington, KY 40511, USA. 7 Department of Neurology, Tufts New England Medical Center, Tufts University, Boston, MA 02111, USA. 8 Department of Neurology, Centre de Recherche du Centre Hospitalier de l'Université de Montreal, University of Montreal, Quebec H2L 4M1, Canada. 9 Clinica Neurologica, Departimento di Scienze Neurologiche, University de Bologna, Via Ugo Foscola, 7,40123 Bologna, Italy. 10 Childrens' Hospital Oakland Research Institute, Oakland, CA 94609, USA. 11 Center for Human Genetics Research, Molecular Physiology and Biophyscis, Vanderbilt University, Nashville, TN 37240, USA. 12 Miami Institute of Human Genetics, Miami, FL 33136, USA 13 Departments of Neurology and Molecular and Cellular Biology, Northwestern Feinberg School of Medicine, Chicago, IL 60611, USA. 14 Department of Neurology, University of Milan Medical School, Dino Ferrari Center, Istituto Auxologico Italiano, Milan 20149, Italy. 15 Department of Biology, Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA.
Retired.
* To whom correspondence should be addressed. E-mail: tkwiatkowski{at}partners.org (T.J.K.); robert.brown{at}umassmed.edu (R.H.B.)
The editors suggest the following Related Resources on Science sites:
In Science Magazine
REPORTS
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, and Christopher E. Shaw (27 February 2009) Science323 (5918), 1208.
[DOI: 10.1126/science.1165942] |Abstract »|Full Text »|PDF »|Supporting Online Material »
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
The TET Family of Proteins: Functions and Roles in Disease.
Sporadic ALS has compartment-specific aberrant exon splicing and altered cell-matrix adhesion biology.
S. J. Rabin, J. M. H. Kim, M. Baughn, R. T. Libby, Y. J. Kim, Y. Fan, R. T. Libby, A. La Spada, B. Stone, and J. Ravits (2009)
Hum. Mol. Genet.
|Abstract »|Full Text »|PDF »
The heritability and genetics of frontotemporal lobar degeneration.
J. D. Rohrer, R. Guerreiro, J. Vandrovcova, J. Uphill, D. Reiman, J. Beck, A. M. Isaacs, A. Authier, R. Ferrari, N. C. Fox, et al. (2009)
Neurology
73, 1451-1456
|Abstract »|Full Text »|PDF »
TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration.
I. Wegorzewska, S. Bell, N. J. Cairns, T. M. Miller, and R. H. Baloh (2009)
PNAS
106, 18809-18814
|Abstract »|Full Text »|PDF »
A new subtype of frontotemporal lobar degeneration with FUS pathology.
M. Neumann, R. Rademakers, S. Roeber, M. Baker, H. A. Kretzschmar, and I. R. A. Mackenzie (2009)
Brain
132, 2922-2931
|Abstract »|Full Text »|PDF »
With or without FUS, it is the anatomy that dictates the dementia phenotype.
S. Weintraub and M. Mesulam (2009)
Brain
132, 2906-2908
|Full Text »|PDF »
Rare missense variants of neuronal nicotinic acetylcholine receptor altering receptor function are associated with sporadic amyotrophic lateral sclerosis.
M. Sabatelli, F. Eusebi, A. Al-Chalabi, A. Conte, F. Madia, M. Luigetti, I. Mancuso, C. Limatola, F. Trettel, F. Sobrero, et al. (2009)
Hum. Mol. Genet.
18, 3997-4006
|Abstract »|Full Text »|PDF »
Axonal Transport Defects in Neurodegenerative Diseases.
G. A. Morfini, M. Burns, L. I. Binder, N. M. Kanaan, N. LaPointe, D. A. Bosco, R. H. Brown Jr, H. Brown, A. Tiwari, L. Hayward, et al. (2009)
J. Neurosci.
29, 12776-12786
|Abstract »|Full Text »|PDF »
Mutations in FUS cause FALS and SALS in French and French Canadian populations.
V. V. Belzil, P. N. Valdmanis, P. A. Dion, H. Daoud, E. Kabashi, A. Noreau, J. Gauthier, for the S2D team, P. Hince, A. Desjarlais, et al. (2009)
Neurology
73, 1176-1179
|Abstract »|Full Text »|PDF »
Analysis of FUS gene mutation in familial amyotrophic lateral sclerosis within an Italian cohort.
N. Ticozzi, V. Silani, A. L. LeClerc, P. Keagle, C. Gellera, A. Ratti, F. Taroni, T. J. Kwiatkowski Jr, D. M. McKenna-Yasek, P. C. Sapp, et al. (2009)
Neurology
73, 1180-1185
|Abstract »|Full Text »|PDF »
Another gene for ALS: Mutations in sporadic cases and the rare variant hypothesis.
Biochemical and genetic evidence for a role of IGHMBP2 in the translational machinery.
M. de Planell-Saguer, D. G. Schroeder, M. C. Rodicio, G. A. Cox, and Z. Mourelatos (2009)
Hum. Mol. Genet.
18, 2115-2126
|Abstract »|Full Text »|PDF »
Reduced expression of the Kinesin-Associated Protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis.
J. E. Landers, J. Melki, V. Meininger, J. D. Glass, L. H. van den Berg, M. A. van Es, P. C. Sapp, P. W. J. van Vught, D. M. McKenna-Yasek, H. M. Blauw, et al. (2009)
PNAS
106, 9004-9009
|Abstract »|Full Text »|PDF »
Retired. 
