• ALS
• genetics

Recently, through homozygosity mapping followed by sequencing of candidate genes in the linkage region, Maruyama et al have discovered that OPTN is a causative gene for amyotrophic lateral sclerosis (ALS).1 They examined a total of 689 Japanese ALS subjects (92 with familial ALS (fALS), including 16 from consanguineous marriages, and 597 with sporadic ALS (sALS)) and identified three types of OPTN mutations.1 The first is a homozygous deletion of exon 5 in two siblings from a consanguineous family. The second is a homozygous nonsense mutation (p.Q398X) in a patient from another consanguineous family. The same homozygous mutation has been found in a sALS subject. The third is a heterozygous missense mutation (p.E478G) in two pairs of siblings from unrelated families. A functional study of p.E478G showed that the mutation lost the NF-κB inhibitory effect of OPTN similar to p.Q398X, supporting its causality.1

To validate the previous result using a different cohort and to further define the spectrum and frequency of the OPTN mutation in ALS, we screened the entire coding region (exons 4–16) and exon–intron boundaries of OPTN mutation in 713 ALS (687 sALS and 26 fALS) patients using a direct sequencing method. Detailed clinical information and experimental methods are described in an online supplementary note. We found 17 kinds of sequence variations (table 1 and online supplementary table 1). All were substitutions of a single nucleotide. There were eight variants in the coding region, and …