ArticleHuman mutation2018
The intellectual disability-associated CAMK2G p.Arg292Pro mutation acts as a pathogenic gain-of-function.
Article in Human mutation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 40 citations in OpenAlex.
- Modeling Synaptic Maturation From Growth Cone to Synapse in Human Organoids.Journal of neurochemistry · 2026Article
- Allele-specific alternative polyadenylation links noncoding genetic variation to Alzheimer's disease risk.bioRxiv : the preprint server for biology · 2026Article
- Nuclear CaMKII Isoforms as Regulators of Transcription: From Developmental to Pathological Persistence.Medical sciences (Basel, Switzerland) · 2025Review
- Biallelic MED29 variants cause pontocerebellar hypoplasia with cataracts.European journal of human genetics : EJHG · 2025Article
- Ligand-induced CaMKIIα hub Trp403 flip, hub domain stacking, and modulation of kinase activity.Protein science : a publication of the Protein Society · 2024Article
- Hippocampal γCaMKII dopaminylation promotes synaptic-to-nuclear signaling and memory formation.bioRxiv : the preprint server for biology · 2024Article
- A recurrent missense variant in the E3 ubiquitin ligase substrate recognition subunit FEM1B causes a rare syndromic neurodevelopmental disorder.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- Role of CAMK2D in neurodevelopment and associated conditions.American journal of human genetics · 2024Article
- autoMEA: machine learning-based burst detection for multi-electrode array datasets.Frontiers in neuroscience · 2024Article
- Editorial: New insights into neurodevelopmental biology and autistic spectrum disorders.Frontiers in neuroscience · 2024Article
- A loss of function variant in AGPAT3 underlies intellectual disability and retinitis pigmentosa (IDRP) syndrome.European journal of human genetics : EJHG · 2023Article
- Synaptic memory and CaMKII.Physiological reviews · 2023Review
- The MAP3K7 gene: Further delineation of clinical characteristics and genotype/phenotype correlations.Human mutation · 2022Article
- Role of CaFrontiers in molecular neuroscience · 2022Review
- Loss of CAMK2G affects intrinsic and motor behavior but has minimal impact on cognitive behavior.Frontiers in neuroscience · 2022Article
- Combination of Genomic and Transcriptomic Approaches Highlights Vascular and Circadian Clock Components in Multiple Sclerosis.International journal of molecular sciences · 2021Article
- Ischemic heart injury leads to HIF1-dependent differential splicing of CaMK2γ.Scientific reports · 2021Article
- The Diagnostic Journey of a Patient with Prader-Willi-Like Syndrome and a Unique HomozygousGenes · 2021Review
- TAOK1 is associated with neurodevelopmental disorder and essential for neuronal maturation and cortical development.Human mutation · 2021Article
- CaMKII controls neuromodulation via neuropeptide gene expression and axonal targeting of neuropeptide vesicles.PLoS biology · 2020Article
Corrections and comments
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Authors and funding
14 authors at 4 institutions in 3 countries.
Funding
Abstract
The abundantly expressed calcium/calmodulin-dependent protein kinase II (CAMK2), alpha (CAMK2A), and beta (CAMK2B) isoforms are essential for learning and memory formation. Recently, a de novo candidate mutation (p.Arg292Pro) in the gamma isoform of CAMK2 (CAMK2G) was identified in a patient with severe intellectual disability (ID), but the mechanism(s) by which this mutation causes ID is unknown. Here, we identified a second, unrelated individual, with a de novo CAMK2G p.Arg292Pro mutation, and used in vivo and in vitro assays to assess the impact of this mutation on CAMK2G and neuronal function. We found that knockdown of CAMK2G results in inappropriate precocious neuronal maturation. We further found that the CAMK2G p.Arg292Pro mutation acts as a highly pathogenic gain-of-function mutation, leading to increased phosphotransferase activity and impaired neuronal maturation as well as impaired targeting of the nuclear CAMK2G isoform. Silencing the catalytic site of the CAMK2G p.Arg292Pro protein reversed the pathogenic effect of the p.Arg292Pro mutation on neuronal maturation, without rescuing its nuclear targeting. Taken together, our results reveal an indispensable function of CAMK2G in neurodevelopment and indicate that the CAMK2G p.Arg292Pro protein acts as a pathogenic gain-of-function mutation, through constitutive activity toward cytosolic targets, rather than impaired targeting to the nucleus.
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