Laboratory for Bone and Joint Diseases, Center for Genomic Medicine, RIKEN, Tokyo 108-8639, Japan.
Hum Mol Genet. 2011 Sep 15;20(18):3684-92. doi: 10.1093/hmg/ddr268. Epub 2011 Jun 10.
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 × 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-β (TGF-β) 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-β signaling and that decreased ZNF512B expression increases susceptibility to ALS.
肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征是运动神经元的选择性丧失。已经报道了几种 ALS 的易感基因；然而，ALS 的病因和发病机制在很大程度上仍然未知。为了鉴定更多的 ALS 易感基因，我们使用基于基因的标签单核苷酸多态性（SNP）进行了大规模的病例对照关联研究。通过逐步筛选方法发现了一个功能 SNP（rs2275294）与 ALS 显著相关（综合 P=9.3×10(-10)，优势比=1.32）。该 SNP 位于 ZNF512B 的增强子区域，ZNF512B 是一种未知生物学功能的转录因子，易感等位基因显示出活性降低和与核蛋白结合减少。ZNF512B 的过表达增加了转化生长因子-β（TGF-β）信号，而敲低则有相反的效果。与对照组相比，ALS 患者脊髓前角运动神经元中 ZNF512B 的表达增加。我们的结果强烈表明 ZNF512B 是 TGF-β 信号的重要正调节剂，而 ZNF512B 表达的降低增加了 ALS 的易感性。
