Amyotrophic lateral sclerosis and structural defects in Cu,Zn superoxide dismutase.


Journal Article

Single-site mutants in the Cu,Zn superoxide dismutase (SOD) gene (SOD1) occur in patients with the fatal neurodegenerative disorder familial amyotrophic lateral sclerosis (FALS). Complete screening of the SOD1 coding region revealed that the mutation Ala4 to Val in exon 1 was the most frequent one; mutations were identified in exons 2, 4, and 5 but not in the active site region formed by exon 3. The 2.4 A crystal structure of human SOD, along with two other SOD structures, established that all 12 observed FALS mutant sites alter conserved interactions critical to the beta-barrel fold and dimer contact, rather than catalysis. Red cells from heterozygotes had less than 50 percent normal SOD activity, consistent with a structurally defective SOD dimer. Thus, defective SOD is linked to motor neuron death and carries implications for understanding and possible treatment of FALS.

Full Text

Cited Authors

  • Deng, HX; Hentati, A; Tainer, JA; Iqbal, Z; Cayabyab, A; Hung, WY; Getzoff, ED; Hu, P; Herzfeldt, B; Roos, RP

Published Date

  • August 1993

Published In

Volume / Issue

  • 261 / 5124

Start / End Page

  • 1047 - 1051

PubMed ID

  • 8351519

Pubmed Central ID

  • 8351519

Electronic International Standard Serial Number (EISSN)

  • 1095-9203

International Standard Serial Number (ISSN)

  • 0036-8075

Digital Object Identifier (DOI)

  • 10.1126/science.8351519


  • eng