2. Academic Validation
  3. Compound heterozygous mutations of NTNG2 cause intellectual disability via inhibition of the CaMKII signaling

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

  • J Genet Genomics. 2024 Aug 14:S1673-8527(24)00198-X. doi: 10.1016/j.jgg.2024.08.001.
Yaoting Chen 1,  Jiang Chen 2,  Lili Liang 1,  Weiqian Dai 1,  Nan Li 1,  Shuangshuang Dong 1,  Yongkun Zhan 3,  Guiquan Chen 4,  Yongguo Yu 5
Affiliations

Affiliations

  • 1 Department of Pediatric Endocrinology and Genetics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine; Shanghai Institute for Pediatric Research, Shanghai 200092, China.
  • 2 Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu 210008, China.
  • 3 Department of Pediatric Endocrinology and Genetics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine; Shanghai Institute for Pediatric Research, Shanghai 200092, China. Electronic address: zhanyongkun@xinhuamed.com.cn.
  • 4 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. Electronic address: chenguiquan@nju.edu.cn.
  • 5 Department of Pediatric Endocrinology and Genetics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine; Shanghai Institute for Pediatric Research, Shanghai 200092, China. Electronic address: yuyongguo@shsmu.edu.cn.
PMID: 39151821 DOI: 10.1016/j.jgg.2024.08.001
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.

Keywords

CaMKII signaling; Intellectual disability; Learning and memory; NTNG2; Synaptic plasticity.

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