A frequent ala 4 to val superoxide dismutase-1 mutation is associated with a rapidly progressive familial amyotrophic lateral sclerosis.
Hum Mol Genet
; 3(6): 981-7, 1994 Jun.
Article
in En
| MEDLINE
| ID: mdl-7951249
ABSTRACT
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 comparison 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.
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Collection:
01-internacional
Health context:
6_ODS3_enfermedades_notrasmisibles
Database:
MEDLINE
Main subject:
Superoxide Dismutase
/
Valine
/
Point Mutation
/
Alanine
/
Amyotrophic Lateral Sclerosis
Type of study:
Risk_factors_studies
Limits:
Animals
/
Humans
/
Middle aged
Language:
En
Journal:
Hum Mol Genet
Year:
1994
Document type:
Article