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Cited by 87Genetics and Neurodevelopmental DisordersGenomics and Rare DiseasesEpilepsy research and treatment

De novo variants in CAMK 2A and CAMK 2B cause neurodevelopmental disorders

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Akita, Tenpei, Aoto, Kazushi, Kato, Mitsuhiro, Shiina, Masaaki, Mutoh, Hiroki, Nakashima, Mitsuko, Kuki, Ichiro, Okazaki, Shin +12 more·2018·Annals of Clinical and Translational Neurology
DOI 10.1002/acn3.528PMC PMC5846454
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Abstract

Objective: α ( CAMK 2A ) and β ( CAMK 2B ) isoforms of Calcium/calmodulin‐dependent protein kinase II (Ca MKII ) play a pivotal role in neuronal plasticity and in learning and memory processes in the brain. Here, we explore the possible involvement of α ‐ and β ‐Ca MKII variants in neurodevelopmental disorders. Methods: Whole‐exome sequencing was performed for 976 individuals with intellectual disability, developmental delay, and epilepsy. The effect of CAMK 2A and CAMK 2B variants on Ca MKII structure and firing of neurons was evaluated by computational structural analysis, immunoblotting, and electrophysiological analysis. Results: We identified a total of five de novo CAMK 2A and CAMK 2B variants in three and two individuals, respectively. Seizures were common to three individuals with CAMK 2A 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 Ca MKII α . 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 Ca MKII α 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 Ca MKII α and Ca MKII β and their autoinhibitory regulation in human brain function, and suggest the enhancement of A‐type K + currents as a possible pathophysiological basis.

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  • The human CaMKII mutations were found by exome sequencing of infants with mild to severe developmental and intellectual disabilities.

    “The mutations were found by exome sequencing of infants with mild to severe developmental and intellectual disabilities.”

    From Synaptic memory and CaMKII (2023) · cites this paper as [430]

    The Abstract Methods report whole-exome sequencing of people with intellectual disability and developmental delay, and the Results report five CAMK2A or CAMK2B variants. The Results describe disability ranging from mild in one person to profound in four. However, Table 1 lists the five individuals as 5–16 years old; although most had symptoms beginning in infancy, the paper does not describe them as infants when the mutations were found. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • None of the human CaMKII mutations blocks generation of constitutive activity comparable to the experimental Thr286A mutation that would enable a test of Thr286 phosphorylation and constitutive CaMKII activity in human memory.

    “However, none blocks generation of constitutive activity, comparable to the experimental Thr286A mutation, that would enable a test of Thr286 phosphorylation and constitutive CaMKII activity in human memory (428–430).”

    From Synaptic memory and CaMKII (2023) · cites this paper as [430]

    The Results section reports increased Thr286/Thr287 phosphorylation in three studied mutants, consistent with those variants not blocking this route to persistent activity. But the paper does not establish that no human CaMKII mutation blocks constitutive activity, compare the variants with experimental Thr286A, or test human memory. Its Discussion also reports decreased Thr286 autophosphorylation for a previously described Glu183Val variant. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • These mutations increase autophosphorylation of T286 (or T287 in some isoforms) that further increases constitutive activity.

    “These in turn increase autophosphorylation of T286 (or T287 in some isoforms) that further increases constitutive activity (429, 430).”

    From Synaptic memory and CaMKII (2023) · cites this paper as [430]

    The Results section reports increased Thr286/Thr287 phosphorylation in three mutants, although two increases were not statistically significant and no phosphorylation signal was observed for a fourth. The Discussion proposes that the variants may increase autophosphorylation and thereby increase Ca²⁺-independent activity; the citing sentence presents that proposed chain as established for the mutations. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Many CaMKII mutations decrease interactions between the kinase surface and the autoinhibitory segment previously shown to increase basal activity that is normally quite low.

    “Many of the mutations decrease interactions between the kinase surface and the autoinhibitory segment previously shown to increase basal activity that is normally quite low.”

    From Synaptic memory and CaMKII (2023) · cites this paper as [430]

    The Results section (page unavailable) predicts that several variants impair interactions between the kinase domain and regulatory segment, and reports increased phosphorylation without stimulation in three mutants. The Introduction describes autoinhibition in the resting state, but the Discussion only suggests that these variants may increase Ca2+-independent activity; it does not establish the claimed increase in basal activity as a direct finding. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Several dozen human mutations in CaMKII have been identified, and their molecular characteristics support many of the biochemical behaviors of CaMKII described above.

    “Several dozen human mutations in CaMKII have been identified, and their molecular characteristics support many of the biochemical behaviors of CaMKII described above.”

    From Synaptic memory and CaMKII (2023) · cites this paper as [430]

    The Discussion reports five de novo CAMK2A/CAMK2B variants identified in this study, not several dozen. The Results link some of those variants to reduced autoinhibition and increased Thr286/Thr287 autophosphorylation, supporting the claim that human variants illuminate CaMKII biochemistry, but not its stated number or breadth. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Cites

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Authors
Akita, T., Aoto, K., Kato, M., Shiina, M., Mutoh, H., Nakashima, M., Kuki, I., Okazaki, S., Magara, S., Shiihara, T., Yokochi, K., Aiba, K., Tohyama, J., Ohba, C., Miyatake, S., Miyake, N., Ogata, K., Fukuda, A., Matsumoto, N., & Saitsu, H.
Affiliations
  • Hamamatsu University (JP)
  • SHOWA Medical University (JP)
  • Yokohama City University (JP)
  • Osaka City General Hospital (JP)
  • Nishi Niigata Chuo National Hospital (JP)
  • Gunma Children's Medical Center (JP)
  • Seirei Mikatabara General Hospital (JP)
  • Toyohashi Municipal Hospital (JP)
Corresponding author
  • Matsumoto, Naomichi
  • Saitsu, Hirotomo
ORCID
Venue
Annals of Clinical and Translational Neurology
Publisher
Wiley
Published
2018-01-29
Volume
5
Issue
3
Pages
280-296
ISSN
2328-9503 (ISSN-L)
DOI
10.1002/acn3.528
PMC
PMC5846454
OpenAlex
W2789974830
Cited by
87
References
5
Citations by year
2026: 8 · 2025: 7 · 2024: 16 · 2023: 11 · 2022: 21 · 2021: 10 · 2020: 8 · 2019: 6
FWCI
3.67
Type
journal article
Language
en
Open access
Licence
Locations
  • Annals of Clinical and Translational Neurology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Japan Agency for Medical Research and Development (17ek0109297h0001)
  • Ministry of Education, Culture, Sports, Science and Technology
  • Japan Society for the Promotion of Science (17H01539, 16H05160, 16H05357, 15K10367, 16K09975, 17K10080, 17K08534)
  • Japan Science and Technology Agency
  • Ministry of Health, Labour and Welfare
  • Takeda Science Foundation
  • Mochida Memorial Foundation for Medical and Pharmaceutical Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
Keywords
CAMK2A, CAMK2B, calcium/calmodulin-dependent protein kinase II, de novo mutations, neurodevelopmental disorders, intellectual disability, developmental delay, epilepsy, splice site mutation, exon skipping, kinase autoinhibition, A-type potassium current, hippocampal neurons, neuronal excitability

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