DOI: 10.1126/science.1166066. Mutations in the <i>FUS/TLS</i> Gene on Chromosome 16 Cause Familial Amyotrophic Lateral Sclerosis

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

10.1126/science.1166066

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

Abstract

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.

Bibliography

Kwiatkowski, T. J., Bosco, D. A., LeClerc, A. L., Tamrazian, E., Vanderburg, C. R., Russ, C., Davis, A., Gilchrist, J., Kasarskis, E. J., Munsat, T., Valdmanis, P., Rouleau, G. A., Hosler, B. A., Cortelli, P., de Jong, P. J., Yoshinaga, Y., Haines, J. L., Pericak-Vance, M. A., Yan, J., â¦ Brown, R. H. (2009). Mutations in the FUS/TLS Gene on Chromosome 16 Cause Familial Amyotrophic Lateral Sclerosis. Science, 323(5918), 1205â1208.

Authors 26

T. J. Kwiatkowski (first)
D. A. Bosco (additional)
A. L. LeClerc (additional)
E. Tamrazian (additional)
C. R. Vanderburg (additional)
C. Russ (additional)
A. Davis (additional)
J. Gilchrist (additional)
E. J. Kasarskis (additional)
T. Munsat (additional)
P. Valdmanis (additional)
G. A. Rouleau (additional)
B. A. Hosler (additional)
P. Cortelli (additional)
P. J. de Jong (additional)
Y. Yoshinaga (additional)
J. L. Haines (additional)
M. A. Pericak-Vance (additional)
J. Yan (additional)
N. Ticozzi (additional)
T. Siddique (additional)
D. McKenna-Yasek (additional)
P. C. Sapp (additional)
H. R. Horvitz (additional)
J. E. Landers (additional)
R. H. Brown (additional)

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In the mutants other amino acids were substituted at certain locations; for example R182Q indicates that arginine at position 182 was replaced by glutamine. Single-letter abbreviations for the amino acid residues are as follows: A Ala; C Cys; D Asp; E Glu; F Phe; G Gly; H His; I Ile; K Lys; L Leu; M Met; N Asn; P Pro; Q Gln; R Arg; S Ser; T Thr; V Val; W Trp; and Y Tyr.
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We gratefully acknowledge I. Carr (University of Leeds UK) for support with AutoSNPa and IBDfinder software A. Storey for assistance with sequencing C. LeClerc for genealogical investigations and D. Crowe for administrative assistance. This work was supported by NIH grants NS050557 (R.H.B. and T.K.) and NS050641 (T.S. R.H.B. J.L. H. and M.P.-V.). R.H.B. also receives support from the Angel Fund the ALS Therapy Alliance the ALS Association Project ALS the Al-Athel ALS Research Foundation and the Pierre L. de Bourgknecht ALS Research Foundation. T.S. also receives support from The Les Turner ALS Foundation Vena E. Schaff ALS Research Fund Harold Post Research Professorship Herbert and Florence C. Wenske Foundation Ralph and Marian Falk Medical Research Trust The David C. Asselin M.D. Memorial Fund Les Turner ALS Foundation/Herbert C. Wenske Foundation Professorship Help America Foundation and the ALS Therapy Alliance Inc. H.R.H. is an investigator of and was supported by the Howard Hughes Medical Institute. R.H.B. is a cofounder of AviTx Inc. which targets development of ALS therapies. R.H.B. and T.J.K. have applied for a patent covering FUS mutations in ALS. We dedicate this report to the memories of Jimmy and Christopher Kennedy Sharon Timlin and Ginny Delvecchio.

Dates

Type	When
Created	16 years, 5 months ago (Feb. 26, 2009, 5:27 p.m.)
Deposited	1 year, 7 months ago (Jan. 10, 2024, 4:54 a.m.)
Indexed	1 week, 4 days ago (Aug. 12, 2025, 6:01 p.m.)
Issued	16 years, 5 months ago (Feb. 27, 2009)
Published	16 years, 5 months ago (Feb. 27, 2009)
Published Print	16 years, 5 months ago (Feb. 27, 2009)

Funders 0

None

BibTeX

@article{Kwiatkowski_2009, title={Mutations in the FUS/TLS Gene on Chromosome 16 Cause Familial Amyotrophic Lateral Sclerosis}, volume={323}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.1166066}, DOI={10.1126/science.1166066}, number={5918}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Kwiatkowski, T. J. and Bosco, D. A. and LeClerc, A. L. and Tamrazian, E. and Vanderburg, C. R. and Russ, C. and Davis, A. and Gilchrist, J. and Kasarskis, E. J. and Munsat, T. and Valdmanis, P. and Rouleau, G. A. and Hosler, B. A. and Cortelli, P. and de Jong, P. J. and Yoshinaga, Y. and Haines, J. L. and Pericak-Vance, M. A. and Yan, J. and Ticozzi, N. and Siddique, T. and McKenna-Yasek, D. and Sapp, P. C. and Horvitz, H. R. and Landers, J. E. and Brown, R. H.}, year={2009}, month=feb, pages={1205–1208} }

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  "abstract": "<jats:p>\n            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\n            <jats:italic>fused in sarcoma/translated in liposarcoma</jats:italic>\n            (\n            <jats:italic>FUS/TLS</jats:italic>\n            ) 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\n            <jats:italic>FUS/TLS</jats:italic>\n            accumulated in the cytoplasm of neurons, a pathology that is similar to that of the gene\n            <jats:italic>TAR DNA-binding protein 43</jats:italic>\n            (\n            <jats:italic>TDP43</jats:italic>\n            ), 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.\n          </jats:p>",
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