单核苷酸变异在一般人群中是常见的基因组变异，其中大部分被认为是无临床重要性的沉默多态性。利用人类诱导多潜能干细胞（hiPSC）大脑器官模型对1.4兆碱基的神经纤维瘤病1型（NF1）缺失综合症进行建模，我们先前发现与NF1基因共删除的细胞因子受体样因子-3（CRLF3）基因作为神经元成熟的主要调节因子。此外，患有NF1和CRLF3L389P变异的儿童有更高的孤独症负担，表明该基因可能对神经功能重要。为了探索该变异的功能后果，我们生成了CRLF3L389P突变型hiPSC系和Crlf3L389P突变基因工程小鼠。尽管该变异不会损害蛋白表达、脑结构或小鼠行为，但CRLF3L389P突变型人类大脑器官模型和小鼠大脑表现出神经元成熟和树突形成的损害。此外，Crlf3L389P突变型小鼠神经元的树突长度和分枝减少，没有轴突缺陷。此外，Crlf3L389P突变型小鼠海马神经元的发放率和突触电流幅度相对于野生型对照组有所降低。综上所述，这些发现确认CRLF3L389P变异具有功能上的有害性，并暗示其可能是神经发育疾病的修饰因子。© 2023年作者。由牛津大学出版社发表。版权所有。如需授权，请发送电子邮件至: journals.permissions@oup.com。

Single nucleotide variants in the general population are common genomic alterations, where the majority are presumed to be silent polymorphisms without known clinical significance. Using human induced pluripotent stem cell (hiPSC) cerebral organoid modeling of the 1.4 megabase Neurofibromatosis type 1 (NF1) deletion syndrome, we previously discovered that the cytokine receptor-like factor-3 (CRLF3) gene, which is co-deleted with the NF1 gene, functions as a major regulator of neuronal maturation. Moreover, children with NF1 and the CRLF3L389P variant have greater autism burden, suggesting that this gene might be important for neurologic function. To explore the functional consequences of this variant, we generated CRLF3L389P-mutant hiPSC lines and Crlf3L389P-mutant genetically engineered mice. While this variant does not impair protein expression, brain structure, or mouse behavior, CRLF3L389P-mutant human cerebral organoids and mouse brains exhibit impaired neuronal maturation and dendrite formation. In addition, Crlf3L389P-mutant mouse neurons have reduced dendrite lengths and branching, without any axonal deficits. Moreover, Crlf3L389P-mutant mouse hippocampal neurons have decreased firing rates and synaptic current amplitudes relative to wild type controls. Taken together, these findings establish the CRLF3L389P variant as functionally deleterious and suggest that it may be a neurodevelopmental disease modifier.© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.