CAMK2A – Intellectual Disability, Autosomal Dominant 53

Calcium/calmodulin-dependent protein kinase II α (CaMKIIα), encoded by CAMK2A, is highly expressed in the brain and critical for synaptic plasticity, learning, and memory. Heterozygous pathogenic variants in CAMK2A underlie Intellectual Developmental Disorder, Autosomal Dominant 53, characterized by global developmental delay, seizures, severe intellectual disability, and epileptic encephalopathy.

Thirteen unrelated individuals have been reported with de novo CAMK2A variants, including nine missense and two splice-site changes identified in a multi-center cohort (n=9 probands) (PMID:29100089) and three additional de novo variants in a pediatric neurodevelopmental screen (n=3 probands) (PMID:29560374). Most recently, a 35-year-old woman with severe epileptic encephalopathy harbored a de novo in-frame deletion c.874_876delCTT (p.Lys292del) that disrupts a critical autoinhibitory segment of CaMKIIα (PMID:37510258).

The spectrum of CAMK2A pathogenic variants comprises at least seven missense substitutions, two canonical splice-site mutations, and an in-frame deletion of Lys292. These alterations cluster within the kinase and association domains, perturbing auto-phosphorylation at Thr286/Thr287 and regulatory interactions. For example, Thr286Pro and Glu183Val variants reduce or abolish Ca2+/CaM-dependent activation and impair neuronal migration in vitro (PMID:29100089).

Functional assays consistently demonstrate a dominant-negative or gain-of-function mechanism. De novo missense mutants alter autophosphorylation kinetics and subcellular targeting in heterologous cells and cultured neurons. FRET-based phenotyping of the recurrent p.Pro212Leu variant reveals facilitated Ca2+/CaM-dependent activation and delayed inactivation in neurons (PMID:36117912). A corresponding P212L knock-in mouse model exhibits exaggerated hippocampal LTP, dendritic spine abnormalities, and learning impairments, recapitulating human intellectual disability phenotypes (PMID:40140673).

No familial segregation beyond de novo cases has been reported, and no studies dispute the CAMK2A–MONDO:0030919 association. The convergent clinical, genetic, and functional data support a pathogenic mechanism driven by dysregulated kinase activity and disrupted synaptic function.

Key Take-home: Heterozygous CAMK2A variants, notably c.874_876delCTT (p.Lys292del), cause autosomal dominant intellectual disability 53 through dominant-negative or gain-of-function effects on CaMKIIα, warranting inclusion of CAMK2A in genetic testing for neurodevelopmental disorders.

References

• Genes • 2023 • Deletion of a Single Lysine Residue at Position 292 of CAMK2A Disrupts Protein Function, Causing Severe Epileptic Encephalopathy and Intellectual Disability. PMID:37510258
• American Journal of Human Genetics • 2017 • De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability. PMID:29100089
• Annals of Clinical and Translational Neurology • 2018 • De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders. PMID:29560374
• Frontiers in Molecular Neuroscience • 2022 • Förster resonance energy transfer-based kinase mutation phenotyping reveals an aberrant facilitation of C²⁺/calmodulin-dependent CaMKIIα activity in de novo mutations related to intellectual disability. PMID:36117912
• Translational Psychiatry • 2025 • A hyper-activatable CAMK2A variant associated with intellectual disability causes exaggerated long-term potentiation and learning impairments. PMID:40140673

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