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Letters to Nature
Nature 362, 59 - 62 (04 March 1993); doi:10.1038/362059a0

Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis

Daniel R. Rosen*, Teepu Siddique, David Patterson, Denise A. Figlewicz§, Peter Sapp*, Afif Hentati, Deirdre Donaldson, Jun Goto§, Jeremiah P. O'Regan*, Han-Xiang Deng, Zohra Rahmani, Aldis Krizus§, Diane McKenna-Yasek*, Annarueber Cayabyab, Sandra M. Gaston*, Ralph Berger, Rudolph E. Tanzi, John J. Halperin#, Brian Herzfeldt, Raymond Van den Bergh**, Wu-Yen Hung, Thomas Bird, Gang Deng, Donald W. Mulder, Celestine Smyth, Nigel G. Laing§§, Edwin Soriano, Margaret A. Pericak–Vance, Jonathan Haines¶¶, Guy A. Rouleau§, James S. Gusella¶¶, H. Robert Horvitz & Robert H. Brown  Jr*##

* Day Neuromuscular Research Laboratory, Massachusetts General Hospital, Room 6627, MGH-East, Building 149,13th Street, Charlestown, Massachusetts 02129, USA
Department of Neurology, Northwestern University Medical School, Chicago, Illinois 60611, USA
Eleanor Roosevelt Institute for Cancer Research and the University of Colorado Health Science Center, Denver, Colorado 80206, USA
§ Center for Research in Neuroscience, McGill University, and the Montreal General Hospital Research Institute, Montreal PQ H3G1A4, Canada
Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Boston, Massachusetts 02139, USA
Laboratory of Genetics and Aging, Neuroscience Center, Massachusetts General Hospital, Boston, Massachusetts 02129, USA
# Department of Neurology, Northshore University Hospital, Manhasset, New York 11030, USA
** Department of Neurology, Universitaire Ziekenhuizen, Leuven 3000, Belgium
Department of Neurology, University of Washington School of Medicine, Seattle, Washington 98195, USA
Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, USA
§§ Australian Neuromuscular Research Institute, Nedlands, Western Australia, Australia
Department of Medicine (Neurology), Duke University Medical Center, Durham, North Carolina 27710, USA
¶¶ Molecular Neurogenetics Laboratory, Neuroscience Center, Massachusetts General Hospital, Boston, Massachusetts 02129, USA
## To whom correspondence should be addressed.

AMYOTROPHIC lateral sclerosis (ALS) is a degenerative disorder of motor neurons in the cortex, brainstem and spinal cord1,2. Its cause is unknown and it is uniformly fatal, typically within five years3. About 10% of cases are inherited as an autosomal dominant trait, with high penetrance after the sixth decade4,5. In most instances, sporadic and autosomal dominant familial ALS (FALS) are clinically similar4,6,7. We have previously shown that in some but not all FALS pedigrees the disease is linked to a genetic defect on chromosome 21q (refs 8,9). Here we report tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O 2 to O2 and H2O2 (ref. 10). Given this linkage and the potential role of free radical toxicity in other neurodenegerative disorders11, we investigated SOD1 as a candidate gene in FALS. We identified 11 different SOD1 missense mutations in 13 different FALS families.

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