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

Research output: Contribution to journalArticle

4725 Citations (Scopus)

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
Externally publishedYes

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Mutation
Genetic Linkage
Penetrance
Poisons
Amyotrophic Lateral Sclerosis
Motor Neurons
Missense Mutation
Pedigree
Superoxides
Genes
Brain Stem
Free Radicals
Chromosomes
Superoxide Dismutase-1
Amyotrophic lateral sclerosis 1

All Science Journal Classification (ASJC) codes

  • General

Cite this

Rosen, D. R., Siddique, T., Patterson, D., Figlewicz, D. A., Sapp, P., Hentati, A., ... 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
Rosen, Daniel R. ; Siddique, Teepu ; Patterson, David ; Figlewicz, Denise A. ; Sapp, Peter ; Hentati, Afif ; Donaldson, Deirdre ; Goto, Jun ; O'Regan, Jeremiah P. ; Deng, Han Xiang ; Rahmani, Zohra ; Krizus, Aldis ; McKenna-Yasek, Diane ; Cayabyab, Annarueber ; Gaston, Sandra M. ; Berger, Ralph ; Tanzi, Rudolph E. ; Halperin, John J. ; Herzfeldt, Brian ; Den Bergh, Raymond Van ; Hung, Wu Yen ; Bird, Thomas ; Deng, Gang ; Mulder, Donald W. ; Smyth, Celestine ; Laing, Nigel G. ; Soriano, Edwin ; Pericak-Vance, Margaret A. ; Haines, Jonathan ; Rouleau, Guy A. ; Gusella, James S. ; Horvitz, H. Robert ; Brown, Robert H. / Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. In: Nature. 1993 ; Vol. 362, No. 6415. pp. 59-62.
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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.",
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Rosen, DR, Siddique, T, Patterson, D, Figlewicz, DA, Sapp, P, Hentati, A, Donaldson, D, Goto, J, O'Regan, JP, Deng, HX, Rahmani, Z, Krizus, A, McKenna-Yasek, D, Cayabyab, A, Gaston, SM, Berger, R, Tanzi, RE, Halperin, JJ, Herzfeldt, B, Den Bergh, RV, Hung, WY, Bird, T, Deng, G, Mulder, DW, Smyth, C, Laing, NG, Soriano, E, Pericak-Vance, MA, Haines, J, Rouleau, GA, Gusella, JS, Horvitz, HR & Brown, RH 1993, 'Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis', Nature, vol. 362, no. 6415, pp. 59-62. https://doi.org/10.1038/362059a0

Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. / Rosen, Daniel R.; Siddique, Teepu; Patterson, David; Figlewicz, Denise A.; Sapp, Peter; Hentati, Afif; Donaldson, Deirdre; Goto, Jun; O'Regan, Jeremiah P.; Deng, Han Xiang; Rahmani, Zohra; Krizus, Aldis; McKenna-Yasek, Diane; Cayabyab, Annarueber; Gaston, Sandra M.; Berger, Ralph; Tanzi, Rudolph E.; Halperin, John J.; Herzfeldt, Brian; Den Bergh, Raymond Van; Hung, Wu Yen; Bird, Thomas; Deng, Gang; Mulder, Donald W.; Smyth, Celestine; Laing, Nigel G.; Soriano, Edwin; Pericak-Vance, Margaret A.; Haines, Jonathan; Rouleau, Guy A.; Gusella, James S.; Horvitz, H. Robert; Brown, Robert H.

In: Nature, Vol. 362, No. 6415, 01.01.1993, p. 59-62.

Research output: Contribution to journalArticle

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T1 - Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis

AU - Rosen, Daniel R.

AU - Siddique, Teepu

AU - Patterson, David

AU - Figlewicz, Denise A.

AU - Sapp, Peter

AU - Hentati, Afif

AU - Donaldson, Deirdre

AU - Goto, Jun

AU - O'Regan, Jeremiah P.

AU - Deng, Han Xiang

AU - Rahmani, Zohra

AU - Krizus, Aldis

AU - McKenna-Yasek, Diane

AU - Cayabyab, Annarueber

AU - Gaston, Sandra M.

AU - Berger, Ralph

AU - Tanzi, Rudolph E.

AU - Halperin, John J.

AU - Herzfeldt, Brian

AU - Den Bergh, Raymond Van

AU - Hung, Wu Yen

AU - Bird, Thomas

AU - Deng, Gang

AU - Mulder, Donald W.

AU - Smyth, Celestine

AU - Laing, Nigel G.

AU - Soriano, Edwin

AU - Pericak-Vance, Margaret A.

AU - Haines, Jonathan

AU - Rouleau, Guy A.

AU - Gusella, James S.

AU - Horvitz, H. Robert

AU - Brown, Robert H.

PY - 1993/1/1

Y1 - 1993/1/1

N2 - 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.

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Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993 Jan 1;362(6415):59-62. https://doi.org/10.1038/362059a0