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

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

来源：Human Molecular Genetics, 2011, 20(18): 3684-3692.

DOI：10.1093/hmg/ddr268

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 = 9.3 x 10(-10), odds ratio = 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-beta (TGF-beta) 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-beta signaling and that decreased ZNF512B expression increases susceptibility to ALS.

• 出版日期2011-9-15
• 单位河北医科大学