Publication Date:
1993-08-20
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Deng, H X -- Hentati, A -- Tainer, J A -- Iqbal, Z -- Cayabyab, A -- Hung, W Y -- Getzoff, E D -- Hu, P -- Herzfeldt, B -- Roos, R P -- New York, N.Y. -- Science. 1993 Aug 20;261(5124):1047-51.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurology, Northwestern University Medical School, Chicago, IL 60611.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8351519" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Sequence
;
Amyotrophic Lateral Sclerosis/enzymology/*genetics
;
Base Sequence
;
Binding Sites
;
Erythrocytes/enzymology
;
Exons
;
Free Radicals/metabolism
;
Humans
;
Models, Molecular
;
Molecular Sequence Data
;
Mutation
;
Protein Folding
;
Protein Structure, Tertiary
;
Superoxide Dismutase/blood/chemistry/*genetics/metabolism
;
X-Ray Diffraction
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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