A NOVEL MUTATION IN CU/ZN SUPEROXIDE-DISMUTASE GENE IN JAPANESE FAMILIAL AMYOTROPHIC-LATERAL-SCLEROSIS

Recently, several missense mutations in the Cu/Zn superoxide dismutase gene (SOD1) have been reported as a putative cause of chromosome-21q-linked familial amyotrophic lateral sclerosis (FALS). We have discovered a novel missense mutation (substitution of Thr for Ala(4)) in exon 1 ((G) under bar CC to (A) under bar CC) in two FALS patients from one Japanese FALS family. No mutations were found in 17 cases of sporadic ALS. The enzyme activity of recombinant fusion protein containing the Cu/Zn superoxide dismutase (SOD) with the Ala(4)-to-Thr mutation was significantly reduced in E. coli. On the other hand, in the expression system in insect cells using Baculovirus, the mutant SOD expressed an enzyme activity as high as wild-type SOD. These results suggest that the stability of SOD with the Ala(4)-to-Thr mutation is disrupted especially in the fusion protein. Autopsy was carried out on one of the two patients, and the pathological findings were typical of FALS with posterior column involvement. These results raise the possibility that mutation of the SOD1 is responsible for FALS with broader pathological involvement. (C) 1994 Academic Press, Inc.