A homozygous loss-of-function <i>CAMK2A</i> mutation causes growth delay, frequent seizures and severe intellectual disability.

Abstract

Calcium/calmodulin-dependent protein kinase II (CAMK2) plays fundamental roles in synaptic plasticity that underlies learning and memory. Here, we describe a new recessive neurodevelopmental syndrome with global developmental delay, seizures and intellectual disability. Using linkage analysis and exome sequencing, we found that this disease maps to chromosome 5q31.1-q34 and is caused by a biallelic germline mutation in <i>CAMK2A</i>. The missense mutation, p.His477Tyr is located in the CAMK2A association domain that is critical for its function and localization. Biochemically, the p.His477Tyr mutant is defective in self-oligomerization and unable to assemble into the multimeric holoenzyme.<i>In vivo</i>, CAMK2A^H477Y failed to rescue neuronal defects in <i>C. elegans</i> lacking <i>unc-43</i>, the ortholog of human <i>CAMK2A. In vitro</i>, neurons derived from patient iPSCs displayed profound synaptic defects. Together, our data demonstrate that a recessive germline mutation in <i>CAMK2A</i> leads to neurodevelopmental defects in humans and suggest that dysfunctional CAMK2 paralogs may contribute to other neurological disorders.