A Novel Human CAMK2A Mutation Disrupts Dendritic Morphology and Synaptic Transmission, and Causes ASD-Related Behaviors
Open accessAbstract
Characterizing the functional impact of novel mutations linked to autism spectrum disorder (ASD) provides a deeper mechanistic understanding of the underlying pathophysiological mechanisms. Here we show that a de novo Glu183 to Val (E183V) mutation in the CaMKIIα catalytic domain, identified in a proband diagnosed with ASD, decreases both CaMKIIα substrate phosphorylation and regulatory autophosphorylation, and that the mutated kinase acts in a dominant-negative manner to reduce CaMKIIα-WT autophosphorylation. The E183V mutation also reduces CaMKIIα binding to established ASD-linked proteins, such as Shank3 and subunits of l -type calcium channels and NMDA receptors, and increases CaMKIIα turnover in intact cells. In cultured neurons, the E183V mutation reduces CaMKIIα targeting to dendritic spines. Moreover, neuronal expression of CaMKIIα-E183V increases dendritic arborization and decreases both dendritic spine density and excitatory synaptic transmission. Mice with a knock-in CaMKIIα-E183V mutation have lower total forebrain CaMKIIα levels, with reduced targeting to synaptic subcellular fractions. The CaMKIIα-E183V mice also display aberrant behavioral phenotypes, including hyperactivity, social interaction deficits, and increased repetitive behaviors. Together, these data suggest that CaMKIIα plays a previously unappreciated role in ASD-related synaptic and behavioral phenotypes. SIGNIFICANCE STATEMENT Many autism spectrum disorder (ASD)-linked mutations disrupt the function of synaptic proteins, but no single gene accounts for >1% of total ASD cases. The molecular networks and mechanisms that couple the primary deficits caused by these individual mutations to core behavioral symptoms of ASD remain poorly understood. Here, we provide the first characterization of a mutation in the gene encoding CaMKIIα linked to a specific neuropsychiatric disorder. Our findings demonstrate that this ASD-linked de novo CAMK2A mutation disrupts multiple CaMKII functions, induces synaptic deficits, and causes ASD-related behavioral alterations, providing novel insights into the synaptic mechanisms contributing to ASD.
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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 [428]
The Introduction and Discussion describe biochemical effects of the human CAMK2A E183V mutation, including reduced kinase activity and altered protein interactions. The paper does not establish that several dozen human CaMKII mutations have been identified or characterize their molecular effects as a group; the Discussion instead focuses on one mutation. No page numbers are available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNone 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 [428]
The Introduction (page unavailable) says Thr286 autophosphorylation generates autonomous CaMKII activity, and the Discussion reports negligible Thr286 autophosphorylation in the human E183V mutant. But the Discussion also says E183V severely impairs catalytic activity more broadly; the paper does not establish that no human mutation selectively blocks constitutive activity like experimental Thr286A, or that such a mutation could test human memory. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThe 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 [428]
The Introduction identifies a de novo CAMK2A mutation in one ASD proband, and the section on knock-in mice mentions whole-exome sequencing in discussing that proband's genetic findings. Table 1 in Additional information lists the proband's age as 5.25 years. The paper does not describe mutations found in multiple infants with mild to severe developmental and intellectual disabilities. (LLM, conf=0.88)
Experimental — accuracy not yet measuredExpression of the E183V mutant in neurons decreases spine density and synaptic transmission.
“Expression of the mutant in neurons decreases spine density and synaptic transmission.”
From Synaptic memory and CaMKII (2023) · cites this paper as [428]
E183V exhibits reduced interactions with GluN2B and other interacting proteins, consistent with a surface groove accommodating both substrates and anchoring proteins.
“Consistent with a surface groove accommodating both substrates and anchoring proteins, it also exhibits reduced interactions with GluN2B and other interacting proteins.”
From Synaptic memory and CaMKII (2023) · cites this paper as [428]
CAMK2A plays vital roles in synaptic plasticity, learning, and memory.
“CAMK2A is a subunit of CAMK2 protein, which is a ubiquitous serine/threonine-protein kinase present in the brain playing vital roles in synaptic plasticity, learning, and memory (Stephenson et al., 2017).”
From miR-142-3p Regulates BDNF Expression in Activated Rodent Microglia Through Its Target CAMK2A (2020) · cites this paper as Stephenson et al., 2017
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“One CaMKII a mutant, E183V, is near the kinase surface, interacting with the autoinhibitory segment, and leads to reduced phosphorylation of exter-nal substrates as well as itself (T286 autophosphorylation) (428).”
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- Authors
- Stephenson, J. R., Wang, X., Perfitt, T. L., Parrish, W. P., Shonesy, B. C., Marks, C. R., Mortlock, D. P., Nakagawa, T., Sutcliffe, J. S., & Colbran, R. J.
- Affiliations
- Vanderbilt University (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2017-01-27
- Volume
- 37
- Issue
- 8
- Pages
- 2216-2233
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC5338762
- OpenAlex
- W2581719304
- Cited by
- 127
- References
- 18
- Citations by year
- 2026: 15 · 2025: 12 · 2024: 20 · 2023: 7 · 2022: 17 · 2021: 17 · 2020: 10 · 2019: 11 · 2018: 10 · 2017: 8
- FWCI
- 7.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association (14PRE18420020, DK20593, 15PRE25110020)
- Vanderbilt University (DK59637, DK20593, DK58404, CA68485, EY08126)
- National Institutes of Health (3p60dk020593-31s3, DK-59637, DK-020593, EY08126, CA68485, DK 20593, DK-58404, CA68485, DK20593, DK58404, DK59637 and EY08126)
- School of Medicine, Vanderbilt University
- Intellectual and Developmental Disabilities Research Center
- University of California, San Francisco (P41-GM103311)
- Vanderbilt Kennedy Center, Vanderbilt University Medical Center
- Vanderbilt Diabetes Research and Training Center, Vanderbilt University Medical Center (DK-20593, DK 020593)
- National Institute of Mental Health (R01MH063232, K01MH107765, F31MH109196, T32MH065215)
- National Eye Institute (P30EY008126)
- National Cancer Institute (P30CA068485)
- National Institute of General Medical Sciences (GM103311, P41GM103311)
- National Institute of Diabetes and Digestive and Kidney Diseases (U2CDK059637, U24DK059637, P30DK058404, P30DK020593)
- National Institute of Neurological Disorders and Stroke (R01NS078291)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083211)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- autism spectrum disorder, CAMK2A, CaMKIIα, de novo mutations, dendritic spine morphology, dendritic branching, excitatory synaptic transmission, autophosphorylation, substrate phosphorylation, dominant negative effect, SHANK3, L-type calcium channels, NMDA receptor, synaptic targeting, hyperactivity, social interaction deficits, repetitive behavior, knock-in mice
- MeSH terms
- Autism Spectrum Disorder, Animals, Brain, Cells, Cultured, Cycloheximide, Dendrites, Disease Models, Animal, Embryo, Mammalian, Exploratory Behavior, Female, Gene Expression Regulation, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Synaptic Transmission, Sialoglycoproteins, Receptors, N-Methyl-D-Aspartate, Rats, Sprague-Dawley, Receptors, AMPA, Excitatory Postsynaptic Potentials, Mice, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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