Compound heterozygous mutations of NTNG2 cause intellectual disability via inhibition of the CaMKII signaling.
J Genet Genomics
; 2024 Aug 14.
Article
in En
| MEDLINE
| ID: mdl-39151821
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
J Genet Genomics
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
China