Abstract
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 Oâ2 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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References
Tandan, R. & Bradley, W. G. Ann. Neurol. 18, 271â280 (1985).
Tandan, R. & Bradley, W. G. Ann. Neurol. 18, 419â431 (1985).
Kurland, L. T. Proc. Staff Meet Mayo Clin. 32, 449â462 (1957).
Mulder, D. W. et al. Neurology 36, 511â517 (1986).
Horton, W. A., Eldridge, R. & Brody, J. A. Neurology 26, 460â464 (1976).
Swerts, L. & Van Den Bergh, R. J. J. genet. Hum. 24, 247â255 (1976).
Huisquinet, H. & Franck, G. Clin. Genet. 18, 109â115 (1980).
Siddique, T. et al. New Engl. J. Med. 324, 1381â1384 (1991).
Siddique, T. et al. Neurology 39, 919â925 (1989).
Fridovich, I. Adv. Enzym. 58, 61â97 (1986).
Olanow, C. W. Ann. Neurol. 32, S2â9 (1992).
Rosen, D. R. et al. Hum. molec. Genet. 1, 547 (1992).
Ott, J. Am. hum. Genet. 28, 528â529 (1976).
Ott, J. Analysis of Human Genetics 203â216 (Johns Hopkins Univ. Press, Baltimore, 1991).
Levanon, D. et al. EMBO J. 77â84 (1985).
Hallewell, R. A. et al. in Superoxide Dismutase in Chemistry, Biology and Medicine (ed. Rotilio, G.) 249â256 (Elsevier, 1986).
Orita, M. et al. Genomics 5, 874â879 (1989).
Dausset, J. et al. Genomics 6, 575â577 (1990).
Beckman, J. S. et al. Proc. natn. Acad. Sci. U.S.A. 87, 1620â1624 (1990).
Imlay, J. A. & Linns, S. Science 240, 1302â1309 (1988).
Philips, J. P. et al. Proc. natn. Acad. Sci. U.S.A. 86, 2761â2765 (1989).
Carlioz, A. & Touati, D. EMBO J. 5, 623â630 (1986).
Farr, S. B., D'Ari, R. & Touati, D. Proc. natn. Acad. Sci. U.S.A. 83, 8268â8272 (1986).
Chang, E. C. et al. J. biol. Chem. 266, 4417â4424 (1991).
Minotti, G. & Aust, S. D. Chem. phys. Lipids 44, 191â208 (1987).
Crapo, J. D. et al. Proc. natn. Acad. Sci. U.S.A. 89, 10405â10409 (1992).
Avraham, K. B. et al. Cell 54, 823â829 (1988).
Yarom, R. et al. J. neurol. Sci. 88, 41â53 (1988).
Avraham, K. B. et al. J. Neurocytol. 20, 208â215 (1991).
Wisnieski, K. et al. Clin. Genet 23, 102â110 (1983).
Ackerman, A. D. et al. New Engl. J. Med. 318, 1666â1669 (1988).
Reynolds, J. F., Wyandt, H. E. & Kelley, T. E. Am. J. hum. Genet. 20, 173â180 (1985).
Hjalmarsson, K. et al. Proc. natn. Acad. Sci. U.S.A. 84, 6340â6344 (1987).
Bewley, G. C. Nucleic Acids Res. 16, 2728 (1988).
Henkle, K. J. et al. Infect. Immun. 59, 2063â2069 (1991).
Perl-Treves, R. et al. Plant molec. Biol. 11, 609â623 (1988).
Bermingham-McDonogh, O. et al. Proc. natn. Acad Sci. U.S.A. 85, 4789â4793 (1988).
Muller, H. in Sixth internat. Congr. Genetics (ed. Jones, D.) 213â255 (Brooklyn Botanic Gardens, Menasha, 1932).
Park, E. & Horvitz, H. R. Genetics 113, 821â852 (1986).
Dryja, T. P. et al. Nature 339, 556â558 (1989).
Herskowitz, I. Nature 329, 219â222 (1987).
Parge, H. E., Hallewell, R. A. & Tainer, J. A. Proc. natn. Acad. Sci. U.S.A. 89, 6109â6113 (1992).
Kitagawa, Y. et al. J. Biochem. 109, 477â485 (1991).
Richardson, J. et al. Proc. natn. Acad. Sci. U.S.A. 72, 1349â1353 (1975).
Creagan, R. et al. Humangenetik 20, 203â209 (1973).
Hendrickson, D. et al. Genomics 8, 736â738 (1990).
Shoulson, I. Ann. N.Y. Acad. Sci. 648, 37â41 (1992).
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Rosen, D., Siddique, T., Patterson, D. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59â62 (1993). https://doi.org/10.1038/362059a0
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DOI: https://doi.org/10.1038/362059a0
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