当前位置: X-MOL 学术Am. J. Hum. Genet. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Loss of function of OTUD7A in the schizophrenia- associated 15q13.3 deletion impairs synapse development and function in human neurons
American Journal of Human Genetics ( IF 9.8 ) Pub Date : 2022-08-05 , DOI: 10.1016/j.ajhg.2022.07.001
Alena Kozlova 1 , Siwei Zhang 2 , Alex V Kotlar 3 , Brendan Jamison 1 , Hanwen Zhang 1 , Serena Shi 4 , Marc P Forrest 5 , John McDaid 6 , David J Cutler 7 , Michael P Epstein 7 , Michael E Zwick 8 , Zhiping P Pang 9 , Alan R Sanders 2 , Stephen T Warren 7 , Pablo V Gejman 2 , Jennifer G Mulle 10 , Jubao Duan 2
Affiliation  

Identifying causative gene(s) within disease-associated large genomic regions of copy-number variants (CNVs) is challenging. Here, by targeted sequencing of genes within schizophrenia (SZ)-associated CNVs in 1,779 SZ cases and 1,418 controls, we identified three rare putative loss-of-function (LoF) mutations in OTU deubiquitinase 7A (OTUD7A) within the 15q13.3 deletion in cases but none in controls. To tie OTUD7A LoF with any SZ-relevant cellular phenotypes, we modeled the OTUD7A LoF mutation, rs757148409, in human induced pluripotent stem cell (hiPSC)-derived induced excitatory neurons (iNs) by CRISPR-Cas9 engineering. The mutant iNs showed a ∼50% decrease in OTUD7A expression without undergoing nonsense-mediated mRNA decay. The mutant iNs also exhibited marked reduction of dendritic complexity, density of synaptic proteins GluA1 and PSD-95, and neuronal network activity. Congruent with the neuronal phenotypes in mutant iNs, our transcriptomic analysis showed that the set of OTUD7A LoF-downregulated genes was enriched for those relating to synapse development and function and was associated with SZ and other neuropsychiatric disorders. These results suggest that OTUD7A LoF impairs synapse development and neuronal function in human neurons, providing mechanistic insight into the possible role of OTUD7A in driving neuropsychiatric phenotypes associated with the 15q13.3 deletion.



中文翻译:

OTUD7A 在精神分裂症相关 15q13.3 缺失中的功能丧失会损害人类神经元的突触发育和功能

在拷贝数变异 (CNV) 的疾病相关大基因组区域内识别致病基因具有挑战性。在这里,通过对 1,779 例 SZ 病例和 1,418 例对照中精神分裂症 (SZ) 相关 CNV 内的基因进行靶向测序,我们在 15q13.3 缺失的 OTU 去泛素化酶 7A ( OTUD7A ) 中发现了三个罕见的假定功能丧失 (LoF) 突变在案例中但在控制中没有。为了将OTUD7A LoF 与任何 SZ 相关的细胞表型联系起来,我们对OTUD7A进行了建模通过 CRISPR-Cas9 工程在人诱导多能干细胞 (hiPSC) 衍生的诱导兴奋性神经元 (iNs) 中产生 LoF 突变 rs757148409。突变体 iNs 显示 OTUD7A 表达降低约 50%,而没有经历无义介导的 mRNA 衰变。突变 iNs 还表现出树突复杂性、突触蛋白 GluA1 和 PSD-95 的密度以及神经元网络活动的显着降低。与突变 iNs 中的神经元表型一致,我们的转录组学分析表明,OTUD7A LoF 下调基因组丰富了与突触发育和功能相关的基因,并且与 SZ 和其他神经精神疾病相关。这些结果表明OTUD7ALoF 会损害人类神经元中的突触发育和神经元功能,从而从机制上深入了解OTUD7A在驱动与 15q13.3 缺失相关的神经精神表型中的可能作用。

更新日期:2022-08-05
down
wechat
bug