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Optineurin mutations in Japanese amyotrophic lateral sclerosis
  1. Aritoshi Iida1,
  2. Naoya Hosono2,
  3. Motoki Sano3,
  4. Tetsumasa Kamei4,
  5. Shuichi Oshima5,
  6. Torao Tokuda6,
  7. Michiaki Kubo2,
  8. Yusuke Nakamura7,
  9. Shiro Ikegawa1
  1. 1Laboratory for Bone and Joint Diseases, Center for Genomic Medicine, RIKEN, Shirokanedai, Minato-ku, Tokyo, Japan
  2. 2Laboratory for Genotyping Development, Center for Genomic Medicine, RIKEN, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, Japan
  3. 3Department of Neurology, Chibanishi General Hospital, Kanegasa-ku, Matsudo, Chiba, Japan
  4. 4Department of Neurology, Chigasaki Tokushukai General Hospital, Saiwai-cho, Chigasaki, Kanagawa, Japan
  5. 5Department of Neurosurgery, Chiba Tokushukai Hospital, Narashino-dai, Funabashi, Chiba, Japan
  6. 6Tokushukai Group, Koujimachi, Chiyoda-ku, Tokyo, Japan
  7. 7Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan
  1. Correspondence to Shiro Ikegawa, Laboratory of Bone and Joint Diseases, Center for Genomic Medicine, RIKEN, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; sikegawa{at}ims.u-tokyo.ac.jp

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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 …

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