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

Molecular Psychiatry volume 30, pages 1497–1509 (2025)Cite this article

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Abstract

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 knock-in mouse model that harbors the K198R mutation in the activation segment of the α subunit of CK2. This region is a mutational hotspot, representing one-third of patients. These mice exhibit behavioral phenotypes that mirror patient symptoms. Homozygous knock-in mice die mid-gestation while heterozygous knock-in mice are born at half of the expected mendelian ratio and are smaller in weight and size than wildtype littermates. Heterozygous knock-in 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 knock-in mice. In congruence, we detect reduced synaptic maturation in hippocampal neurons and attenuated long-term potentiation in the hippocampus of knock-in mice. Taken together, heterozygous knock-in mice (CK2αK198R/+) 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.

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Fig. 1: Gross phenotyping of K198R/+ mice.
Fig. 2: Expression and activity of CK2 in K198R/+ mice.
Fig. 3: Mass spectrometric analysis of phosphoproteome.
Fig. 4: Synapse analysis in hippocampus.
Fig. 5: Synaptic potentiation of hippocampal CA1 field EPSPs ex vivo.
Fig. 6: Behavioral characterization.

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Acknowledgements

We thank Dr Sampath Rangasamy, TGen, Az for donating patient fibroblasts. We thank David Boulet, Deniz Erden, Walifa Waqar, Ludivine Therreau, Dr Gwenaelle LePen, Dr Virginie Tolle, Juliette Forget and the animal facility team. Imaging was carried out at the NeurImag facility (Inserm 1266 and Université de Paris). We thank Sésame Région Ile-de-France for funding the Zeiss880 Confocal/Airyscan system. This work was supported by the CSNK2A1 foundation (HR, JJ), by a MSCA-fellowship (894207, HR), French Ministry of Research BioSPC (JMCG, DB), Fondation pour la Recherche Médicale EQU202003010457 (RP) and Agence Nationale de la Recherche ANR-18-CE370020-01 (RP).

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Authors and Affiliations

  1. Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Laboratory of Signaling mechanisms in neurological disorders, 75014, Paris, France

    Jose M. Cruz-Gamero, Demetra Ballardin, Barbara Lecis, Chun-Lei Zhang, Rebecca Piskorowski & Heike Rebholz

  2. GHU-Paris Psychiatrie et Neurosciences, Hôpital Sainte Anne, F-75014, Paris, France

    Barbara Lecis & Heike Rebholz

  3. Center for Molecular Biophysics-CNRS UPR 4301, Rue Charles Sadron, Orléans, France

    Laetitia Cobret & Severine Morisset-Lopez

  4. Institute of Pharmaceutical and Medicinal Chemistry, Pharmacampus, University of Münster, Münster, Germany

    Alexander Gast & Joachim Jose

  5. Inserm, Institut du Cerveau, Plateforme ICM-Quant, Paris, France

    Dominique Langui

  6. Université Paris Cité, CNRS,Institut Jacques Monod, Paris, France

    Guillaume Chevreux

  7. Center of Neurodegeneration, Faculty of Medicine, Danube Private University, Krems, Austria

    Heike Rebholz

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  1. Jose M. Cruz-Gamero
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Contributions

HR and JMCG designed, performed the studies, analyzed data, and wrote the manuscript. DB, CLZ, and GC collected and analyzed data, and contributed to the manuscript. BL, LC, AG, and DL contributed to data collection and analysis. RP, JJ, and SML analyzed data and contributed to the manuscript. All authors approved the manuscript.

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Correspondence to Heike Rebholz.

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All methods were performed in accordance with the relevant guidelines and regulations. Animal procedures were approved by the French Ministry of Higher Education and are in accordance with the local IACUC CEEA-34 Université Paris Cité, Apafis No. 28822-2022011423502271 and No. 28822-2019081015485048.

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Cruz-Gamero, J.M., Ballardin, D., Lecis, B. et al. Missense mutation in the activation segment of the kinase CK2 models Okur-Chung neurodevelopmental disorder and alters the hippocampal glutamatergic synapse. Mol Psychiatry 30, 1497–1509 (2025). https://doi.org/10.1038/s41380-024-02762-8

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