Compound heterozygous mutations of <i>NTNG2</i> cause intellectual disability via inhibition of the CaMKII signaling

Yaoting Chen; Jiang Chen; Lili Liang; Weiqian Dai; Nan Li; Shuangshuang Dong; Yongkun Zhan; Guiquan Chen; Yongguo Yu

doi:10.1016/j.jgg.2024.08.001

Volume 51 Issue 11

Nov. 2024

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Article Navigation > Journal of Genetics and Genomics > 2024 > 51(11): 1204-1214

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

doi: 10.1016/j.jgg.2024.08.001

a. Department of Pediatric Endocrinology and Genetics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China;
b. Shanghai Institute for Pediatric Research, Shanghai 200092, China;
c. Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu 210008, China;
d. MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, Jiangsu 210061, China

Funds:

We also thank sources of research funding in this study including National Key R&D Program of China (2022YFC2703400 to Y.G.Y.), National Natural Science Foundation of China (82001209 to S.S.D., 82271904 and 82070914 to Y.G.Y.), Shanghai Municipal Commission of Health and Family Planning (20204Y0451 to S.S.D.), Shanghai Scientific and Technological Innovation Action Plan (20YF1440600 to S.S.D.), and Shanghai Natural Science Foundation of China (21ZR1452700 to Y.K.Z.).

Received Date: 2024-05-22
Accepted Date: 2024-08-05
Rev Recd Date: 2024-08-04

Available Online: 2025-06-06

Publish Date: 2024-08-14

Abstract

Abstract

Netrin-G2 is a membrane-anchored protein 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.(Trp202X) 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 Ntng2^{R183Afs/W202X} mice exhibit hypotonia and impaired learning and memory. We find that the levels of CaMKII and p-GluA1^Ser831 are decreased, and excitatory postsynaptic transmission and long-term potentiation are impaired. To increase the activity of CaMKII, the mutant mice receive 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.
- CaMKII signaling,
- Intellectual disability,
- NTNG2,
- Synaptic plasticity,
- Learning and memory

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References(42)

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