Mutations of schizophrenia risk gene SETD1A dysregulate synaptic function in human neurons

作者：Xiao Su, Hanwen Zhang, Hong Yan, Qian Yang, Le Wang, Tiffany Le, Jiayi Liu, Lasya Cheruvu, Emily Labour, Siwei Zhang, Karla Méndez‐Maldonado, Anat Kreimer, Hongjun Song, Guo‐li Ming, Jubao Duan, Zhiping P. Pang · 发表于：Molecular Psychiatry · 年份：2025 · DOI：10.1038/s41380-025-03246-z · 被引用次数：6 · 研究领域：CRISPR and Genetic Engineering、RNA Research and Splicing、Genetics and Neurodevelopmental Disorders

Abstract Schizophrenia (SCZ) is a complex neuropsychiatric disorder associated with both common risk variants of small effect sizes and rare risk variants of high penetrance. Rare premature open reading frame (ORF) termination variants in SETD1A (SET Domain Containing 1A) show a strong association with SCZ; however, it remains largely unclear how rare premature ORF termination variants in SETD1A contribute to the pathophysiology of SCZ. To understand the impact of SETD1A rare premature ORF termination variants in human neurons, we CRISPR/Cas9-engineered five isogenic pairs of human induced pluripotent stem cells (iPSCs), with a recurrent heterozygous patient-specific premature ORF termination mutation c.4582-2delAG in two donor lines and a heterozygous frameshift mutation c.4596_4597insG (p. Leu1533fs) in three donor lines. These two mutations are predicted to cause a premature stop codon in exon 16 of SETD1A , leading to SETD1A haploinsufficiency. We found that these presumably loss-of-function (LoF) mutations caused the SETD1A mRNAs to be degraded by nonsense-mediated decay (NMD), accompanied by a reduction of full-length SETD1A protein level in iPSCs. We then characterized the morphological, electrophysiological, and transcriptomic impacts of SETD1A +/− LoF mutations in iPSC-derived human excitatory neurons induced by NGN2. We found that the SETD1A +/− exon-16 LoF mutations altered dendrite complexity, dysregulated synaptic transmission, and synaptic plasticity, likely by ...