Clinical characteristics of SOD1 gene mutations in UK families with ALS.

Five to ten percent of patients with ALS have a family history of the disease, inheritance is usually autosomal dominant. Mutations of the SOD1 gene were first identified in a proportion of families with ALS by Rosen et al. The SOD1 gene encodes the enzyme copper zinc superoxide dismutase. Patients were studied from throughout the UK, where more than one individual in the family had ALS. Clinical history and examination of the individual and family were obtained, and DNA extracted from leukocytes of whole blood samples. Mutations were identified by standard sequencing methods. To date, 12 different mutations of SOD1 have been identified in 17 different families, representing around 20% of all ALS families studied. The mutations were mainly single base substitutions - H48Q, G72S, G93R, G93V, E100G, D101N, D101G, G108V, I113T, D125H, I149T - and also an insertion mutation - 132insTT - leading to a premature stop codon. The mutations were present in exons 2-5. We did not identify mutations in exon 1, although these have been identified by others in different patient samples. We have identified SOD1 mutations in around 20% of UK families with ALS studied. This is similar to that reported in other populations. Mutations have now been identified in all exons of SOD1. The individual mutations do not precisely predict disease severity, and generally it is difficult to give a specific prognosis based on the individuals' SOD1 mutations. We continue to investigate the possible pathogenic mechanisms of the SOD1 mutations. We have studied the neuropathology in patients with SOD1 mutations. We are also performing linkage studies to identify the genes involved in the 80% of families where an SOD1 mutation has not been identified.

Familial ALS is associated with mutations in all exons of SOD1: a novel mutation in exon 3 (Gly72Ser).

Mutations of the SOD1 gene, which encodes the enzyme copper/zinc superoxide dismutase, are associated with familial amyotrophic lateral sclerosis (ALS). SOD1 consists of five exons, and over 50 different mutations have been described involving exons 1,2,4 and 5. The absence of mutations in exon 3 has been attributed to a critical function of this exon, its integrity being necessary for the toxic effect of mutant SOD1, and it has been suggested that such mutations may be lethal rather than leading to adult onset disease. We identified the heterozygote mutation Gly72Ser (exon 3) in a family with two individuals affected by ALS. SOD enzyme activity was reduced by 45% when measured in erythrocytes indicating reduced enzyme activity, or reduced stability of the mutant protein. These findings indicate that exon 3 is not a privileged region from mutation; that all five exons should be investigated when seeking SOD1 mutations in human disease; and may help in a better understanding of the pathogenicity of these mutations in ALS.