Relevance to Autism

A de novo missense variant in the CAMK2A gene (c.548A>T;p.Glu183Val) was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; additional functional characterizaton in Stephenson et al., 2017 demonstrated the p.Glu183Val missense variant disrupted multiple CaMKII functions, induced synaptic deficits and caused ASD-related behavioral alterations in mice. A de novo intronic variant adjacent to the splice donor site of the CAMK2A gene was identified in another ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; in silico analysis performed in Kury et al., 2017 predicted that this variant resulted in skipping of in-frame CAMK2A exon 8 and a partial loss of the CAMK2A kinase domain. Kury et al., 2017 reported an additional 12 individuals with intellectual disability and CAMK2A variants, several of which were experimentally shown to be either loss-of-function or gain-of-function variants; three of these individuals also presented with autistic features.

Molecular Function

The product of this gene belongs to the serine/threonine protein kinases family, and to the Ca(2+)/calmodulin-dependent protein kinases subfamily. The alpha chain encoded by this gene is required for hippocampal long-term potentiation (LTP) and spatial learning. In addition to its calcium-calmodulin (CaM)-dependent activity, this protein can undergo autophosphorylation, resulting in CaM-independent activity.

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Model Summary

Mice with Camk2a-E183V mutation have reduced forebrain Camk2a levels, with lower abundance in the synaptic subcellular fractions. The Camk2a-E183V mice also exhibit hyperactivity, social interaction deficits, and increased repetitive behaviors.

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