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 BerghWu 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*

*Corresponding author for this work

Research output: Contribution to journalArticle

4916 Scopus citations

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 O-2 to O 2 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.

Original languageEnglish (US)
Pages (from-to)59-62
Number of pages4
JournalNature
Volume362
Issue number6415
DOIs
StatePublished - Jan 1 1993

ASJC Scopus subject areas

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    Rosen, D. R., Siddique, T., Patterson, D., Figlewicz, D. A., Sapp, P., Hentati, A., Donaldson, D., Goto, J., O'Regan, J. P., Deng, H. X., Rahmani, Z., Krizus, A., McKenna-Yasek, D., Cayabyab, A., Gaston, S. M., Berger, R., Tanzi, R. E., Halperin, J. J., Herzfeldt, B., ... Brown, R. H. (1993). Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature, 362(6415), 59-62. https://doi.org/10.1038/362059a0