Exon 5 encoded domain is not required for the toxic function of mutant SOD1 but essential for the dismutase activity: Identification and characterization of two new SOD1 mutations associated with familial amyotrophic lateral sclerosis

James S. Zu, Han Xiang Deng, Terence P. Lo, Hiroshi Mitsumoto, Mohamed S. Ahmed, Wu Yen Hung, Zi Jian Cai, John A. Tainer, Teepu Siddique*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Two new mutations in the gene encoding cytoplasmic Cu,Zn superoxide dismutase (SOD1) have been discovered in patients with familial amyotrophic lateral sclerosis (FALS). These mutations result in the truncation of most of the polypeptide segment encoded by exon 5, one by the formation of a stop codon in codon 126 (L126Z) and the other by inducing alternative splicing in the mRNA (splicing junction mutation). These two mutants of SOD1 result in a FALS phenotype similar to that observed in patients with missense mutations in the SOD1 gene, establishing that exon 5 is not required for the novel toxic functions of mutant SOD1 associated with ALS. These mutant enzymes are present at very low levels in FALS patients, suggesting elevated toxicity compared to mutant enzymes with single site substitutions. This increased toxicity likely arises from the extreme structural and functional changes in the active site channel, β-barrel fold, and dimer interface observed in the mutant enzymes, including the loss of native dismutase activity. In particular, the truncation of the polypeptide chain dramatically opens the active site channel, resulting in a marked increase in the accessibility and flexibility of the metal ions and side chain ligands of the enzyme active site. These structural changes are proposed to cause a decrease in substrate specificity and an increase in the catalysis of harmful chemical reactions such as peroxidation.

Original languageEnglish (US)
Pages (from-to)65-71
Number of pages7
JournalNeurogenetics
Volume1
Issue number1
DOIs
StatePublished - 1997

Keywords

  • Amyotrophic lateral sclerosis (ALS)
  • Cu
  • Zn superoxide dismutase (SOD1)

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Cellular and Molecular Neuroscience

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