NOVEL MUTATIONS IN AN OTHERWISE STRICTLY CONSERVED DOMAIN OF CUZN SUPEROXIDE-DISMUTASE

All mutations in the human gene for CuZn superoxide dismutase (CuZnSOD ) reported to date are associated with the disease amyotrophic lateral sclerosis (ALS). These mutations, mostly of a familial nature (ALS 1, MIM 105400), span all of the coding region of this enzyme except for a highly conserved centrally located domain that includes all of exon III. We describe the identification and characterization of two mutati ons in this region, both found in mice. One mutation, a glutamate to l ysine amino acid substitution was found in position 77 (E77K) of the s train SOD1/Ei distributed by the Jackson Laboratory. The other mutatio n, a lysine to glutamate substitution at position 70 (K70E) of a human transgene, was discovered in mouse line TgHS/SF-155. Enzyme activity measurements and heterodimer analysis of the CuZn SOD variant in SOD1/ Ei suggest a mild loss of activity, which differs from the enzyme acti vity losses detected in patients with autosomal dominant ALS 1. Simila rly, the presence of the mutant transgene in TgHS/SF 155 does not prod uce any phenotypic manifestations.