Molecular characteristics

CAMK2B encodes the beta 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. CAMK2B 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 Thr287 phosphorylation site required for autonomous (calcium independent) activity, a variable domain containing the F-actin binding domain, and an association domain necessary for assembly of the (mixed) holoenzyme with 10-12 CAMK2 subunits. CAMK2B is shown to have both enzymatic as well as structural functions, regulating amongst others the subcellular localisation of CAMK2A (with which it forms heteromers) and through this being an important player in plasticity, learning and memory.

In the initial study, seven different heterozygous CAMK2B variants were identified in 10 unrelated individuals with intellectual disability. Their de novo status was confirmed for all of them. The majority of the variants were missense substitutions (4/7) mainly 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 two variants affected canonical splice sites.