Abstract
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 language | English |
|---|---|
| Article number | ddr268 |
| Pages (from-to) | 3684-3692 |
| Number of pages | 9 |
| Journal | Human molecular genetics |
| Volume | 20 |
| Issue number | 18 |
| DOIs | |
| Publication status | Published - 01-09-2011 |
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All Science Journal Classification (ASJC) codes
- Molecular Biology
- Genetics
- Genetics(clinical)
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A functional variant in ZNF512B is associated with susceptibility to amyotrophic lateral sclerosis in Japanese. / 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; Sobue, Gen; Nakamura, Yusuke; Ikegawa, Shiro.
In: Human molecular genetics, Vol. 20, No. 18, ddr268, 01.09.2011, p. 3684-3692.Research output: Contribution to journal › Article
TY - JOUR
T1 - A functional variant in ZNF512B is associated with susceptibility to amyotrophic lateral sclerosis in Japanese
AU - Iida, Aritoshi
AU - Takahashi, Atsushi
AU - Kubo, Michiaki
AU - Saito, Susumu
AU - Hosono, Naoya
AU - Ohnishi, Yozo
AU - Kiyotani, Kazuma
AU - Mushiroda, Taisei
AU - Nakajima, Masahiro
AU - Ozaki, Kouichi
AU - Tanaka, Toshihiro
AU - Tsunoda, Tatsuhiko
AU - Oshima, Shuichi
AU - Sano, Motoki
AU - Kamei, Tetsumasa
AU - Tokuda, Torao
AU - Aoki, Masashi
AU - Hasegawa, Kazuko
AU - Mizoguchi, Koichi
AU - Morita, Mitsuya
AU - Takahashi, Yuji
AU - Katsuno, Masahisa
AU - Atsuta, Naoki
AU - Watanabe, Hirohisa
AU - Tanaka, Fumiaki
AU - Kaji, Ryuji
AU - Nakano, Imaharu
AU - Kamatani, Naoyuki
AU - Tsuji, Shoji
AU - Sobue, Gen
AU - Nakamura, Yusuke
AU - Ikegawa, Shiro
PY - 2011/9/1
Y1 - 2011/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80052253329&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80052253329&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddr268
DO - 10.1093/hmg/ddr268
M3 - Article
C2 - 21665992
AN - SCOPUS:80052253329
VL - 20
SP - 3684
EP - 3692
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 18
M1 - ddr268
ER -