Mutation analysis of the optineurin gene in familial amyotrophic lateral sclerosis

Mutations in the optineurin gene (OPTN) have been reported in rare familial and sporadic amyotrophic lateral sclerosis (ALS) cases. It is yet to be established whether mutations segregate with dominantly inherited familial ALS. We therefore performed mutation analysis in a cohort of 96 autosomal dominant ALS families. A novel heterozygous nonsynonymous variant (c.218C > T, S73L) was identified in one patient; however, analysis in the extended pedigree demonstrated that this variant was inherited from an unaffected parent. The variant was absent in 480 control individuals. The affected serine residue is highly conserved and its substitution is predicted to alter phosphorylation. Despite this, our evidence indicates that this variant is unlikely to play a pathogenic role in the disease. Cell and animal models will be required to functionally support the pathogenic role of OPTN mutations.