A frequent ala 4 to val superoxide dismutase-1 mutation is associated with a rapidly progressive familial amyotrophic lateral sclerosis

• Published in: Human molecular genetics 1994-06, Vol.3 (6), p.981-987
• Main Authors: Rosen, Daniel R., Bowling, Allen C., Patterson, David, Usdin, Ted B., Sapp, Peter, Mezey, Eva, McKenna-Yasek, Diane, O'Regan, Jerimiah, Rahmani, Zohra, Ferrante, Robert J., Brownstein, Michael J., Kowall, Neil W., Beal, M.Flint, Horvitz, H.Robert, Brown, Robert H.
• Format: Article
• Language: English
• Subjects: Age of Onset; Alanine; Amino Acid Sequence; amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - enzymology; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - mortality; Animals; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA Primers; enzymatic activity; Exons; Humans; In Situ Hybridization; Isoenzymes - genetics; man; Medical sciences; Middle Aged; Molecular Sequence Data; mutation; Neurology; Point Mutation; Polymerase Chain Reaction; Sequence Homology, Amino Acid; superoxide dismutase; Superoxide Dismutase - genetics; Survival Analysis; Valine
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/3.6.981

Familial amyotrophic lateral sclerosis (FALS), a degenerative disorder of motor neurons, is associated with mutations in the Cu/Zn superoxide dismutase gene SOD1 in some affected families. We confirm a recently reported ala4→val mutation in exon 1 of the SOD1 gene and report that this mutation is both the most commonly detected of all SOD1 mutations and among the most clinically severe. By comparision with our other FALS families, the exon 1 mutation is associated with reduced survival time after onset: 1.2 years, as compared to 2.5 years for all other FALS patients. We also demonstrate that SOD1 is prominently expressed in normal motor neurons and that neural expression of SOD1 is not prevented by this exon 1 mutation. Assays of SOD1 enzymatic activity in extracts from red blood cells, lymphoblastoid cells, and brain tissues revealed an approximately 50% reduction in activity of cytosolic SOD1 in patients with this mutation compared to normal individuals. By contrast, patients with sporadic ALS had normal levels of SOD1 enzymatic activity. Why this SOD1 mutation causes motor neuron death in FALS remains to be established. While it may be that FALS is a consequence of loss of SOD1 function, it is also possible that motor neuron death in this dominantly inherited disease occurs because the mutations confer an additional, cytotoxic function on the SOD1 protein.