上海交通大学余永国等研究人员合作发现，NTNG2的复合杂合突变通过抑制CaMKII信号通路引起智力障碍。相关论文于2024年8月14日在线发表在《遗传学报》上。

研究人员发现了c.547delC, p.(Arg183Alafs*186)和c.605G>A, p.(Trp202*)的复合杂合体突变在NTNG2中引起发育迟缓、智力残疾、张力低下和面部畸形的综合征。为了阐明潜在的细胞和分子机制，研究人员利用CRISPR-Cas9技术构建了表达R183Afs和W202X突变的敲入小鼠模型。

研究人员发现，Ntng2^{R183Afs/W202X}小鼠表现出张力减退和学习记忆受损。研究人员发现CaMKII和p-GluA1^Ser831水平降低，兴奋性突触后传递和长时程增强受损。为了增加CaMKII的活性，突变小鼠接受了CaMKII激动剂DCP-LA腹腔注射，并表现出改善的认知功能。总之，该发现揭示了NTNG2缺乏如何导致认知能力和突触可塑性受损的分子机制。

研究人员表示，Netrin-G2是一种膜锚定蛋白，已知在神经元回路发育和突触组织中起关键作用。

附：英文原文

Title: Compound heterozygous mutations of NTNG2 cause intellectual disability via inhibition of the CaMKII signaling

Author: Yongkun Zhan a, Guiquan Chen c, Yongguo Yu a

Issue&Volume: 2024/08/14

Abstract: Netrin-G2 is a membrane-anchored protein and is known to play critical roles in neuronal circuit development and synaptic organization. In this study, we identify compound heterozygous mutations of c.547delC, p.(Arg183Alafs*186) and c.605G>A, p.(Trp202*) in NTNG2 causing a syndrome exhibiting developmental delay, intellectual disability, hypotonia, and facial dysmorphism. To elucidate the underlying cellular and molecular mechanisms, CRISPR-Cas9 technology is employed to generate a knock-in mouse model expressing the R183Afs and W202X mutations. We report that the Ntng2R183Afs/W202X mice exhibit hypotonia and impaired learning and memory. We find that levels of CaMKII and p-GluA1Ser831 are decreased and excitatory postsynaptic transmission and long-term potentiation are impaired. To increase the activity of CaMKII, the mutant mice have received intraperitoneal injections of DCP-LA, a CaMKII agonist, and show improved cognitive function. Together, our findings reveal molecular mechanisms of how NTNG2 deficiency leads to impairments of cognitive ability and synaptic plasticity.

DOI: 10.1016/j.jgg.2024.08.001

Source: https://www.sciencedirect.com/science/article/abs/pii/S167385272400198X