In the present study, we identified exonic mutation and intronic alterations in the SOD1 gene in a Korean family with FALS. Patients with these mutations have differing clinical onset symptoms and anticipation (i.e., acceleration of the age at onset in successive generations).
The subpopulation of this family reported on previously, who had only G10V mutations, showed mostly lower motor neuron involvement, ascending progression, and rapid disease progression.15
However, as a whole, SOD1
mutations in this family resulted in different phenotypes, although anticipation was a unique feature, especially in the males. The observed anticipation may have been influenced by observer bias given that (1) the deduction of clinical onset in generation II based on anamnestic data can cause overinterpretation and (2) other (younger) family members who were not affected at the time of this study may develop the disease later. Mutation testing in all unaffected family members is necessary to completely resolve this issue, but ethical issues make this difficult. Further follow-up is warranted in at least one younger sister (IV-7) in the family who had a mutation of the SOD1
gene and was alive without any symptoms.
Anticipation has been reported in several FALS families,17-19
but its molecular basis remains speculative. It has been suggested that anticipation can result from additional genetic effects or from environmental factors.4
An amino acid substitution at position 84 in Japanese and Italian families was found to be associated with generational anticipation, which might also have been associated with several factors such as being male and exposure to toxicants.17,18
The presence of a G93S mutation in another Japanese family suggests that ethnicity influences this genetic mutation.19
The G10V mutation was reported to occur exclusively in Korea, whereas other synonymous glycine10
mutations were found in other ethnic groups.12
Therefore, factors that generate anticipation in our family may be related to an ethnic-genetic interaction in addition to the effect of being male, although the role of the particular codon mutation itself cannot be excluded.
In our family, the pathogenic role of the intronic variations in the SOD1
gene remains unclear. With few exceptions, mutations in the SOD1
gene destabilize the structure of the SOD1 protein through metal-ion loss or perturbations of protein folding, and these destabilized SOD1 proteins either aggregate or turn over more rapidly relative to the wild-type enzyme.20
The proband and his elder sister (carrying mutations in the exons and introns of the SOD1
gene) showed clinical symptoms that differed from those of previously reported family members, especially at the initial stage of the disease.15
One possible explanation for the phenotypic differences and anticipation is intronic changes to the G10V mutation having an cumulative effect over generations. It is also possible that the intronic alterations of the SOD1
gene contribute to the manifestations of FALS in other ways, such as by altering the pattern of gene expression by disturbing RNA splicing, or causing conformation changes of the gene product. However, since we did not functionally analyze the SOD1 enzyme activity or SOD1 at the protein level, further investigations are needed to elucidate the role of the intronic variations. In addition, it cannot be ruled out that these intronic variations represent a simple single-nucleotide polymorphism in the Korean population. Additional studies in a larger sample are required for confirmation.
In summary, we have described a family with FALS that showed autosomal-dominant inheritance and two distinct genetic alterations in Cu/Zn-SOD1, in which the affected family members exhibited different phenotypes and anticipation.