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Science 27 February 2009:
Vol. 323. no. 5918, pp. 1205 - 1208
DOI: 10.1126/science.1166066
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Reports

Mutations in the FUS/TLS Gene on Chromosome 16 Cause Familial Amyotrophic Lateral Sclerosis

T. J. Kwiatkowski, Jr.,1* D. A. Bosco,1,2 A. L. LeClerc,1,2 E. Tamrazian,1 C. R. Vanderburg,3 C. Russ,1,4 A. Davis,1 J. Gilchrist,5 E. J. Kasarskis,6 T. Munsat,7{dagger} P. Valdmanis,8 G. A. Rouleau,8 B. A. Hosler,1 P. Cortelli,9 P. J. de Jong,10 Y. Yoshinaga,10 J. L. Haines,11 M. A. Pericak-Vance,12 J. Yan,13 N. Ticozzi,1,2,14 T. Siddique,13 D. McKenna-Yasek,1 P. C. Sapp,1,15 H. R. Horvitz,15 J. E. Landers,1,2 R. H. Brown, Jr.1,2*

Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder. Ten percent of cases are inherited; most involve unidentified genes. We report here 13 mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene on chromosome 16 that were specific for familial ALS. The FUS/TLS protein binds to RNA, functions in diverse processes, and is normally located predominantly in the nucleus. In contrast, the mutant forms of FUS/TLS accumulated in the cytoplasm of neurons, a pathology that is similar to that of the gene TAR DNA-binding protein 43 (TDP43), whose mutations also cause ALS. Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and 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.

{dagger} Retired.

* To whom correspondence should be addressed. E-mail: tkwiatkowski{at}partners.org (T.J.K.); robert.brown{at}umassmed.edu (R.H.B.)

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