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 CAMK2A. 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.In vivo, CAMK2AH477Y failed to rescue neuronal defects in C. elegans lacking unc-43, the ortholog of human CAMK2A. In vitro, neurons derived from patient iPSCs displayed profound synaptic defects. Together, our data demonstrate that a recessive germline mutation in CAMK2A leads to neurodevelopmental defects in humans and suggest that dysfunctional CAMK2 paralogs may contribute to other neurological disorders.
Highlights
Calcium/calmodulin-dependent protein kinase II (CAMK2) is a calcium-activated serine/threonine kinase that is extremely abundant in the brain, comprising as much as 0.3% of the total brain protein content (Bennett et al, 1983)
The results showed that the two children with the condition had inherited a recessive mutation in a gene called CAMK2A
We could not detect any selfassociation between FLAG- CAMK2AH477Y and HA- CAMK2AH477Y (Figure 3D, Lane 16). These results suggest that the missense p.H477Y partially disrupts the self-association between identical CAMK2A molecules, which had been shown to be required for holoenzyme assembly
Summary
Calcium/calmodulin-dependent protein kinase II (CAMK2) is a calcium-activated serine/threonine kinase that is extremely abundant in the brain, comprising as much as 0.3% of the total brain protein content (Bennett et al, 1983). Experiments in Caenorhabditis elegans, a roundworm commonly used to study neurons, confirmed that the mutation inherited by the children caused similar neurological defects in the worms Taken together, these experiments suggest that the children’s condition is caused by the mutation in both copies of the CAMK2A gene. Global developmental delay in infants is defined as a significant functional delay in two or more developmental domains including gross and fine motor function, speech and language, cognition, social development and personal skills (Quality Standards Subcommittee of the American Academy of Neurology et al, 2003) These defects are detected at an early age in children age five years or under, and can persist throughout life (Shevell, 2008). For many patients with global neuro-developmental delay, the genetic etiology remains unknown
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