Zinc finger protein 804A (ZNF804A) and verbal deficits in individuals with autism
Zinc finger protein 804A (ZNF804A) and verbal deficits in individuals with autism
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DOI：
10.1503/jpn.130126
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发表时间：
2014-09-01
影响因子：
4.3
通讯作者：
Mori, Norio
中科院分区：
文献类型：
--
作者：
Anitha, Ayyappan;Thanseem, Ismail;Mori, Norio
背景：在一项自闭症的全基因组关联研究中，锌指蛋白804A(ZNF804A)单核苷酸多态(SNPs)被发现与自闭症患者的言语缺陷存在名义上的关联。锌指蛋白804a拷贝数变异(CNV)也在自闭症患者中观察到。此外，ZNF804A被认为参与了心理理论(Tom)任务，心理理论缺陷被认为是自闭症患者面临的沟通和社会挑战的罪魁祸首。我们推测ZNF804A可能是自闭症的危险基因。方法：对841个有1个或多个自闭症成员的家系进行ZNF804A基因关联和CNV检测。我们比较了ZNF804A在自闭症患者(n=8)和对照组(n=13)死后脑中的表达。我们还在体外评估了ZNF804A沉默对几个已知与言语效率和社会认知有关的基因表达的影响。结果：我们发现rs7603001与自闭症有名义上的关联(p=0.018)。在言语缺陷的自闭症患者的家庭中，这种联系更强(p=0.008)。我们观察了7例自闭症言语障碍男童的ZNF804A CNV。在ZNF804A基因敲除细胞中，突触体相关蛋白25 kDa(SNAP25)的表达较对照组降低(p=0.009)。ZNF804A(p=0.009)和SNAP25(p=0.009)在自闭症患者的前扣带回表达减少。ZNF804A和SNAP25在ACG中的表达呈显著正相关(p<；0.001)。局限性：研究局限性包括我们死后大脑的小样本量。结论：ZNF804A基因可能是调节自闭症患者言语特征相关中间表型的潜在候选基因。
Background: In a genome-wide association study of autism, zinc finger protein 804A (ZNF804A) single nucleotide polymorphisms (SNPs) were found to be nominally associated in verbally deficient individuals with autism. Zinc finger protein 804A copy number variations (CNVs) have also been observed in individuals with autism. In addition, ZNF804A is known to be involved in theory of mind (ToM) tasks, and ToM deficits are deemed responsible for the communication and social challenges faced by individuals with autism. We hypothesized that ZNF804A could be a risk gene for autism. Methods: We examined the genetic association and CNVs of ZNF804A in 841 families in which 1 or more members had autism. We compared the expression of ZNF804A in the postmortem brains of individuals with autism (n = 8) and controls (n = 13). We also assessed in vitro the effect of ZNF804A silencing on the expression of several genes known to be involved in verbal efficiency and social cognition. Results: We found that rs7603001 was nominally associated with autism (p = 0.018). The association was stronger (p = 0.008) in the families of individuals with autism who were verbally deficient (n = 761 families). We observed ZNF804A CNVs in 7 verbally deficient boys with autism. In ZNF804A knockdown cells, the expression of synaptosomal-associated protein, 25kDa (SNAP25) was reduced compared with controls (p = 0.009). The expression of ZNF804A (p = 0.009) and SNAP25 (p = 0.009) were reduced in the anterior cingulate gyrus (ACG) of individuals with autism. There was a strong positive correlation between the expression of ZNF804A and SNAP25 in the ACG (p < 0.001). Limitations: Study limitations include our small sample size of postmortem brains. Conclusion: Our results suggest that ZNF804A could be a potential candidate gene mediating the intermediate phenotypes associated with verbal traits in individuals with autism.