De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders

被引：65

作者：

Akita, Tenpei ^{[1
]}

Aoto, Kazushi ^{[2
]}

Kato, Mitsuhiro ^{[3
]}

Shiina, Masaaki ^{[4
]}

Mutoh, Hiroki ^{[1
]}

Nakashima, Mitsuko ^{[2
,5
]}

Kuki, Ichiro ^{[6
]}

Okazaki, Shin ^{[6
]}

Magara, Shinichi ^{[7
]}

Shiihara, Takashi ^{[8
]}

Yokochi, Kenji ^{[9
,10
]}

Aiba, Kaori ^{[10
]}

Tohyama, Jun ^{[7
]}

Ohba, Chihiro ^{[5
]}

Miyatake, Satoko ^{[5
]}

Miyake, Noriko ^{[5
]}

Ogata, Kazuhiro ^{[4
]}

Fukuda, Atsuo ^{[1
]}

Matsumoto, Naomichi ^{[5
]}

Saitsu, Hirotomo ^{[2
]}

机构：

[1] Hamamatsu Univ Sch Med, Dept Neurophysiol, Higashi Ku, 1-20-1 Handayama, Hamamatsu, Shizuoka 4313192, Japan

[2] Hamamatsu Univ Sch Med, Dept Biochem, Higashi Ku, 1-20-1 Handayama, Hamamatsu, Shizuoka 4313192, Japan

[3] Showa Univ, Sch Med, Dept Pediat, Shinagawa Ku, 1-5-8 Hatanodai, Tokyo 1428666, Japan

[4] Yokohama City Univ, Dept Biochem, Grad Sch Med, Kanazawa Ku, 3-9 Fukuura, Yokohama, Kanagawa 2360004, Japan

[5] Yokohama City Univ, Dept Human Genet, Grad Sch Med, Kanazawa Ku, 3-9 Fukuura, Yokohama, Kanagawa 2360004, Japan

[6] Osaka City Gen Hosp, Pediat Med Care Ctr, Dept Pediat Neurol, Miyakojima Ku, 2-13-22 Miyakojimahondori, Osaka 5340021, Japan

[7] Nishi Niigata Chuo Natl Hosp, Dept Pediat, Epilepsy Ctr, Nishi Ku, 1-14-1 Masago, Niigata 9502085, Japan

[8] Gunma Childrens Med Ctr, Dept Neurol, 779 Shimohakoda,Hokkitsu Machi, Shibukawa, Gunma 3778577, Japan

[9] Seirei Mikatahara Gen Hosp, Dept Pediat Neurol, Kita Ku, 3453 Mikatahara Cho, Hamamatsu, Shizuoka 4338558, Japan

[10] Toyohashi Municipal Hosp, Dept Pediat, 50 Hachikennishi,Aotake Cho, Toyohashi, Aichi 4418570, Japan

来源：

ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY | 2018年 / 5卷 / 03期

基金：

日本学术振兴会;

关键词：

LONG-TERM POTENTIATION; CORTICAL PYRAMIDAL NEURONS; KV4.2 CHANNEL EXPRESSION; PROTEIN-KINASE-II; POSTSYNAPTIC DENSITY; SYNAPTIC PLASTICITY; MUTATIONS; EXCITABILITY; ENCEPHALOPATHY;

D O I：

10.1002/acn3.528

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Objective: alpha (CAMK2A) and beta (CAMK2B) isoforms of Calcium/calmodulin-dependent protein kinase II (CaMKII) play a pivotal role in neuronal plasticity and in learning and memory processes in the brain. Here, we explore the possible involvement of alpha- and beta-CaMKII variants in neurodevelopmental disorders. Methods: Whole-exome sequencing was performed for 976 individuals with intellectual disability, developmental delay, and epilepsy. The effect of CAMK2A and CAMK2B variants on CaMKII structure and firing of neurons was evaluated by computational structural analysis, immunoblotting, and electrophysiological analysis. Results: We identified a total of five de novo CAMK2A and CAMK2B variants in three and two individuals, respectively. Seizures were common to three individuals with CAMK2A variants. Using a minigene splicing assay, we demonstrated that a splice site variant caused skipping of exon 11 leading to an in-frame deletion of the regulatory segment of CaMKII. By structural analysis, four missense variants are predicted to impair the interaction between the kinase domain and the regulatory segment responsible for the autoinhibition of its kinase activity. The Thr286/Thr287 phosphorylation as a result of release from autoinhibition was increased in three mutants when the mutants were stably expressed in Neuro-2a neuroblastoma cells. Expression of a CaMKII alpha mutant in primary hippocampal neurons significantly increased A-type K+ currents, which facilitated spike repolarization of single action potentials. Interpretation: Our data highlight the importance of CaMKII alpha and CaMKII beta and their autoinhibitory regulation in human brain function, and suggest the enhancement of A-type K+ currents as a possible pathophysiological basis.

引用

页码：280 / 296

页数：17

共 34 条

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