CAMK2A encodes the alpha subunit of dodecameric holoenzyme CAMK2. The CAMK2 family consists of four different highly homologous isozymes (CAMK2A, CAMK2B, CAMK2D and CAMK2G), of which CAMK2A and CAMK2B are the most abundant proteins expressed in the mammalian brain. CAMK2A consists of four distinct domains: a catalytic domain containing the active-site required for CAMK2 kinase activity, a regulatory domain comprising the calcium-calmodulin binding site and the autoinhibitory domain including the Thr286 phosphorylation site required for autonomous (calcium independent) activity, a variable domain, and an association domain necessary for assembly of the (mixed) holoenzyme with 10-12 CAMK2 subunits. CAMK2A is shown to be the “molecular memory switch” in neurons, since it can convert short influxes of Calcium into long-lasting changes in the strength of synaptic connections, thereby being essential for learning, memory and plasticity.
In the initial study, 12 different heterozygous CAMK2A variants were identified in 14 unrelated individuals with intellectual disability. Their de novo status was confirmed for 11 of them (paternal DNA sample was unavailable in one family). The majority of the variants were missense substitutions (8/12) located in the catalytic domain of the protein, and, to a lesser extent, the regulatory domain and are thought to affect the kinase activity of the protein. One variant induced a premature stop codon, whereas three variants affected canonical splice sites.