1. Compound heterozygous mutations of NTNG2 cause intellectual disability via inhibition of the CaMKII signaling.
- Author
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Chen Y, Chen J, Liang L, Dai W, Li N, Dong S, Zhan Y, Chen G, and Yu Y
- Subjects
- Animals, Mice, Humans, Male, Female, Disease Models, Animal, Neuronal Plasticity genetics, Intellectual Disability genetics, Intellectual Disability pathology, Calcium-Calmodulin-Dependent Protein Kinase Type 2 genetics, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Heterozygote, Mutation genetics, Signal Transduction genetics
- 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-GluA1Ser831 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., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.) more...- Published
- 2024
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