DIVERSE PHENOTYPES AND PHENOTYPE SEVERITY IN DIFFERENT KNOCKIN MOUSE MODELS OF OKUR CHUNG NEURODEVELOPMENTAL SYNDROME SUGGEST COMPLEXITY OF DISEASE MECHANISMS

Okur-Chung Neurodevelopmental Syndrome (OCNDS) is caused by de novo variants in CSNK2A1, the gene encoding the catalytic α subunit of heterotetrameric kinase CK2, that is abundantly expressed in the brain and plays a critical role in brain development and physiology.
Variants, in their majority missense variants, are present across the entire coding sequence, however, several mutation hotspots exist. The mechanism of disease etiology is still unknown, with the strongest argument for haploinsuffiency stemming from the existence of full gene deletion variants, while a dominant negative mechanism appears less likely since holoenzymes consisting of mutant and WT CK2a are still active towards a substrate peptide. We propose here a mechanism that involves neomorphic properties in some OCNDS CK2a variants, based on mass spectrometry analysis. It is highly plausible that the variability of mutants entails different mechanisms, since mutant proteins vary in diverse parameters, such as stability and subcellular localization, kinase activity and alterations in substrate binding and their interactome.
To start addressing the impact of individual variants in vivo, we compared four different mouse lines reproducing different genetic variants, CK2α K198R, R47G and R312W and CK2a+/- mice. While all homozygous mice are non-viable, heterozygous mice appear healthy and fertile. We detect differences in the bulk phosphoproteome of brain tissue, in CK2a activity and stability. Accordingly, mice present differential behavioral profiles, with propensity to seizure induction being the major converging phenotype. We propose that different variants may exercise their symptom profile and symptom severity via diverse disease mechanisms.