@article{86a63438f68d430fa21fc7512b295192,
title = "A functional variant in ZNF512B is associated with susceptibility to amyotrophic lateral sclerosis in Japanese",
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.",
author = "Aritoshi Iida and Atsushi Takahashi and Michiaki Kubo and Susumu Saito and Naoya Hosono and Yozo Ohnishi and Kazuma Kiyotani and Taisei Mushiroda and Masahiro Nakajima and Kouichi Ozaki and Toshihiro Tanaka and Tatsuhiko Tsunoda and Shuichi Oshima and Motoki Sano and Tetsumasa Kamei and Torao Tokuda and Masashi Aoki and Kazuko Hasegawa and Koichi Mizoguchi and Mitsuya Morita and Yuji Takahashi and Masahisa Katsuno and Naoki Atsuta and Hirohisa Watanabe and Fumiaki Tanaka and Ryuji Kaji and Imaharu Nakano and Naoyuki Kamatani and Shoji Tsuji and Gen Sobue and Yusuke Nakamura and Shiro Ikegawa",
note = "Funding Information: We thank all ALS patients who participated in the study. We also thank all members of Japanese ALS Association and all participating doctors and staff from collaborating institutes. The DNA samples used for this research were provided from the Leading Project for Personalized Medicine in the Ministry of Education, Culture, Sports, Science and Technology, Japan, and from JaCALS. JaCALS members included Drs M. Ito, J. Senda (Nagoya University), H. Takano (Niigata University), A. Kawata, H. Hayashi (Tokyo Metropolitan Neurological Hospital), I. Aiba (Higashi Nagoya National Hospital), A. Taniguchi (Mie University), Y. Izumi (University of Tokushima), M. Sakai, M. Konagaya (Suzuka National Hospital), H. Mizusawa (Tokyo Medical and Dental University), T. Yuasa (Kamagaya General Hospital), T. Fujita (Takumikai Neurology Clinic), M. Ikeda, K. Okamoto (Gunma University), S. Akimoto, H. Sasaki (Hokkaido University), T. Imai (Miyagi National Hospital) and S. Kuzuhara (National Center Hospital of Neurology and Psychiatry). Funding Information: This work was supported by grants from the Leading Project of Ministry of Education, Culture, Sports, Science and Technology Japan; Health and Labour, Sciences Research Grants for Research on Measures for Intractable Diseases and Comprehensive Research on Aging and Health from the Ministry of Health, Labour and Welfare, Japan; and by a Grant-in-Aid for Scientific Research (C) (19500314) from the Ministry of Education, Culture, Sports, Science and Technology Japan (A.I.).",
year = "2011",
month = sep,
doi = "10.1093/hmg/ddr268",
language = "English",
volume = "20",
pages = "3684--3692",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "18",
}