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 O2 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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Author information

Affiliations

  1. Day Neuromuscular Research Laboratory, Massachusetts General Hospital, Room 6627, MGH-East, Building 149,13th Street, Charlestown, Massachusetts 02129, USA

    • Daniel R. Rosen
    • , Peter Sapp
    • , Jeremiah P. O'Regan
    • , Diane McKenna-Yasek
    • , Sandra M. Gaston
    •  & Robert H. Brown Jr
  2. Department of Neurology, Northwestern University Medical School, Chicago, Illinois 60611, USA

    • Teepu Siddique
    • , Afif Hentati
    • , Han-Xiang Deng
    • , Annarueber Cayabyab
    • , Brian Herzfeldt
    • , Wu-Yen Hung
    • , Gang Deng
    • , Celestine Smyth
    •  & Edwin Soriano
  3. Eleanor Roosevelt Institute for Cancer Research and the University of Colorado Health Science Center, Denver, Colorado 80206, USA

    • David Patterson
    • , Deirdre Donaldson
    • , Zohra Rahmani
    •  & Ralph Berger
  4. Center for Research in Neuroscience, McGill University, and the Montreal General Hospital Research Institute, Montreal PQ H3G1A4, Canada

    • Denise A. Figlewicz
    • , Jun Goto
    • , Aldis Krizus
    •  & Guy A. Rouleau
  5. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Boston, Massachusetts 02139, USA

    • Peter Sapp
    • , Jeremiah P. O'Regan
    •  & H. Robert Horvitz
  6. Laboratory of Genetics and Aging, Neuroscience Center, Massachusetts General Hospital, Boston, Massachusetts 02129, USA

    • Sandra M. Gaston
    •  & Rudolph E. Tanzi
  7. Department of Neurology, Northshore University Hospital, Manhasset, New York 11030, USA

    • John J. Halperin
  8. Department of Neurology, Universitaire Ziekenhuizen, Leuven 3000, Belgium

    • Raymond Van den Bergh
  9. Department of Neurology, University of Washington School of Medicine, Seattle, Washington 98195, USA

    • Thomas Bird
  10. Department of Neurology, Mayo Clinic, Rochester, Minnesota 55905, USA

    • Donald W. Mulder
  11. Australian Neuromuscular Research Institute, Nedlands, Western Australia, Australia

    • Nigel G. Laing
  12. Department of Medicine (Neurology), Duke University Medical Center, Durham, North Carolina 27710, USA

    • Margaret A. Pericak–Vance
  13. Molecular Neurogenetics Laboratory, Neuroscience Center, Massachusetts General Hospital, Boston, Massachusetts 02129, USA

    • Jonathan Haines
    •  & James S. Gusella
  14. To whom correspondence should be addressed.

    • Robert H. Brown Jr

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