In:
Annals of Clinical and Translational Neurology, Wiley, Vol. 5, No. 3 ( 2018-03), p. 280-296
Abstract:
α ( CAMK 2A ) and β ( CAMK 2B ) isoforms of Calcium/calmodulin‐dependent protein kinase II (Ca MKII ) play a pivotal role in neuronal plasticity and in learning and memory processes in the brain. Here, we explore the possible involvement of α ‐ and β ‐Ca MKII variants in neurodevelopmental disorders. Methods Whole‐exome sequencing was performed for 976 individuals with intellectual disability, developmental delay, and epilepsy. The effect of CAMK 2A and CAMK 2B variants on Ca MKII structure and firing of neurons was evaluated by computational structural analysis, immunoblotting, and electrophysiological analysis. Results We identified a total of five de novo CAMK 2A and CAMK 2B variants in three and two individuals, respectively. Seizures were common to three individuals with CAMK 2A variants. Using a minigene splicing assay, we demonstrated that a splice site variant caused skipping of exon 11 leading to an in‐frame deletion of the regulatory segment of Ca MKII α . By structural analysis, four missense variants are predicted to impair the interaction between the kinase domain and the regulatory segment responsible for the autoinhibition of its kinase activity. The Thr286/Thr287 phosphorylation as a result of release from autoinhibition was increased in three mutants when the mutants were stably expressed in Neuro‐2a neuroblastoma cells. Expression of a Ca MKII α mutant in primary hippocampal neurons significantly increased A‐type K + currents, which facilitated spike repolarization of single action potentials. Interpretation Our data highlight the importance of Ca MKII α and Ca MKII β and their autoinhibitory regulation in human brain function, and suggest the enhancement of A‐type K + currents as a possible pathophysiological basis.
Type of Medium:
Online Resource
ISSN:
2328-9503
,
2328-9503
DOI:
10.1002/acn3.2018.5.issue-3
Language:
English
Publisher:
Wiley
Publication Date:
2018
detail.hit.zdb_id:
2740696-9
