A functional variant in ZNF512B is associated with susceptibility to amyotrophic lateral sclerosis in Japanese

Aritoshi Iida, Atsushi Takahashi, Michiaki Kubo, Susumu Saito, Naoya Hosono, Yozo Ohnishi, Kazuma Kiyotani, Taisei Mushiroda, Masahiro Nakajima, Kouichi Ozaki, Toshihiro Tanaka, Tatsuhiko Tsunoda, Shuichi Oshima, Motoki Sano, Tetsumasa Kamei, Torao Tokuda, Masashi Aoki, Kazuko Hasegawa, Koichi Mizoguchi, Mitsuya MoritaYuji Takahashi, Masahisa Katsuno, Naoki Atsuta, Hirohisa Watanabe, Fumiaki Tanaka, Ryuji Kaji, Imaharu Nakano, Naoyuki Kamatani, Shoji Tsuji, Gen Sobue, Yusuke Nakamura, Shiro Ikegawa

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)


Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Several susceptibility genes for ALS have been reported; however, ALS etiology and pathogenesis remain largely unknown. To identify further ALS-susceptibility genes,we conducted a large-scale case-control association study using gene-based tag single-nucleotide polymorphisms (SNPs). A functional SNP (rs2275294) was found to be significantly associated with ALS through a stepwise screening approach (combined P 5 9.3 3 10210, odds ratio 5 1.32). The SNP was located in an enhancer region of ZNF512B, a transcription factor of unknown biological function, and the susceptibility allele showed decreased activity and decreased binding to nuclear proteins. ZNF512B over-expression increased transforming growth factor-b (TGF-b) signaling, while knockdown had the opposite effect. ZNF512B expression was increased in the anterior horn motor neurons of the spinal cord of ALS patients when compared with controls. Our results strongly suggest that ZNF512B is an important positive regulator of TGF-b signaling and that decreased ZNF512B expression increases susceptibility to ALS.

Original languageEnglish
Article numberddr268
Pages (from-to)3684-3692
Number of pages9
JournalHuman molecular genetics
Issue number18
Publication statusPublished - 09-2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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