首页|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

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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.547deIC,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 Ntng2R183Afs/W202X mice exhibit hypo-tonia 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.

CaMKⅡ signalingIntellectual disabilityNTNG2Synaptic plasticityLearning and memory

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

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Department of Pediatric Endocrinology and Genetics,Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200092,China

Shanghai Institute for Pediatric Research,Shanghai 200092,China

Department of Neurology,Nanjing Drum Tower Hospital,Affiliated Hospital of Medical School,Nanjing University,Nanjing,Jiangsu 210008,China

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

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2024

10.1016/j.jgg.2024.08.001

遗传学报
中国遗传学会 中国科学院遗传与发育生物学研究所

遗传学报

CSTPCD
影响因子：0.821
ISSN：1673-8527
年,卷(期)：2024.51(11)