人类新基因ZNF418的研究初报

根据计算机克隆的ZNF418基因序列设计引物,从人类胚胎心脏文库中克隆了一个人类新KRAB/C2H2型锌指基因,经国际基因命名委员会批准命名为ZNF418。该基因位于染色体19 q13.43,编码蛋白由676个氨基酸残基组成的、含有1个KRAB框和17个连续排列的C2H2型锌指的蛋白质。Northern杂交的结果表明该基因在多种成人组织中表达;亚细胞定位研究证明ZNF418蛋白主要分布在胞核中。这些结果提示该基因编码一种潜在的转录因子。     

The effect of psychosis associated CACNA1C,and its epistasis with ZNF804A,on brain function

CACNA1C‐rs1006737 and ZNF804A‐rs1344706 polymorphisms are among the most robustly associated with schizophrenia (SCZ) and bipolar disorder (BD), and recently with brain phenotypes. As these patients show abnormal verbal fluency (VF) and related brain activation, we asked whether the latter was affected by these polymorphisms (alone and in interaction)—to better understand how they might induce risk. We recently reported effects on functional VF‐related (for ZNF804A‐rs1344706) and structural (for both) connectivity. We genotyped and fMRI‐scanned 54 SCZ, 40 BD and 80 controls during VF. With SPM, we assessed the main effect of CACNA1C‐rs1006737, and its interaction with ZNF804A‐rs1344706, and their interaction with diagnosis, on regional brain activation and functional connectivity (psychophysiological interactions—PPI). Using public data, we reported effects of CACNA1C‐rs1006737 and diagnosis on brain expression. The CACNA1C‐rs1006737 risk allele was associated with increased activation, particularly in the bilateral prefronto‐temporal cortex and thalamus; decreased PPI, especially in the left temporal cortex; and gene expression in white matter and the cerebellum. We also found unprecedented evidence for epistasis (interaction between genetic polymorphisms) in the caudate nucleus, thalamus, and cingulate and temporal cortical activation; and CACNA1C up‐regulation in SCZ and BD parietal cortices. Some effects were dependent on BD/SCZ diagnosis. All imaging results were whole‐brain, voxel‐wise, and familywise‐error corrected. Our results support evidence implicating CACNA1C and ZNF804A in BD and SCZ, adding novel imaging evidence in clinical populations, and of epistasis—which needs further replication. Further scrutiny of the inherent neurobiological mechanisms may disclose their potential as putative drug targets.