Missense mutation in the activation segment of the kinase CK2 models Okur Chung neurodevelopmental disorder and alters the hippocampal glutamatergic synapse

Exome sequencing has enabled the identification of causative genes of monogenic forms of autism, amongst them, in 2016, CSNK2A1, the gene encoding the catalytic subunit of the kinase CK2, linking this kinase to Okur-Chung Neurodevelopmental Syndrome (OCNDS), a newly described neurodevelopmental condition with many symptoms resembling those of autism spectrum disorder.

Thus far, no preclinical model of this condition exists. Here we describe a knockin mouse model that harbors the K198R mutation in the activation segment of the kinase. This region is a mutational hotspot, representing one-third of patients. These mice exhibit behavioral phenotypes that mirror patient symptoms. Homozygous knock-in (KI) mice die mid-gestation while heterozygous KI mice are born at half of the expected mendelian ratio and are smaller in weight and size than wildtype littermates. Heterozygous KI mice showed alterations in cognition and memory-assessing paradigms, enhanced stereotypies, altered circadian activity patterns, and nesting behavior. Phosphoproteome analysis from brain tissue revealed alterations in the phosphorylation status of major pre- and postsynaptic proteins of heterozygous KI mice. In congruence, we detect reduced synaptic maturation in hippocampal neurons and attenuated long-term potentiation in the hippocampus of KI mice. Taken together, K198R KI mice exhibit significant face validity, presenting ASD-relevant phenotypes, synaptic deficits and alterations in synaptic plasticity, all of which strongly validate this line as a mouse model of OCNDS.