CNS TISSUE CU ZN SUPEROXIDE-DISMUTASE (SOD1) MUTATIONS IN MOTOR-NEURON DISEASE (MND)/

DNA extracted from CNS tissue of 79 cases of motor neurone disease (MN D) was screened by single strand conformation analysis (SSCA) and hete roduplex analysis (HA) for mutations in the Cu/Zn superoxide dismutase (SOD1) gene. The aims were to determine whether somatic mutations of SOD1 may underlie some cases of MND and to characterize the genetic ab normalities by sequencing, for subsequent correlation with the molecul ar pathological phenotype. In 3 cases a point mutation was found in ex on 4: E100G in one familial case, and I113T in two cases (one familial , one sporadic). Two cases had previously undescribed mutations in the 3' untranslated region (3'UTR) of SOD1 and one case had a single base substitution in the intronic sequence upstream from exon 2. None of t hese patients had a positive family history. Non-CNS tissue was availa ble for 3 out of the 6 cases in whom changes were found. In all 3 the same changes were consistently found in both CNS and non-CNS tissue, e xcluding the presence of somatic mutations in SOD1. We investigated ma ny MND blood samples and normal controls for the presence of the 3'UTR deletions. We found the 4 bp deletion in 1/90 sporadic MND patients a nd 1/209 non-MND controls. If the 3'UTR deletions are pathogenic, they would have to operate via a loss of the function mechanism, and furth er work is necessary to define their significance.