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


Journal

Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835

Informations de publication

Date de publication:
04 Oct 2024
Historique:
received: 20 10 2023
accepted: 23 09 2024
revised: 14 09 2024
medline: 5 10 2024
pubmed: 5 10 2024
entrez: 4 10 2024
Statut: aheadofprint

Résumé

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 (CK2α

Identifiants

pubmed: 39367055
doi: 10.1038/s41380-024-02762-8
pii: 10.1038/s41380-024-02762-8
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
ID : 894207

Informations de copyright

© 2024. The Author(s), under exclusive licence to Springer Nature Limited.

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Auteurs

Jose M Cruz-Gamero (JM)

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

Demetra Ballardin (D)

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

Barbara Lecis (B)

Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Laboratory of Signaling mechanisms in neurological disorders, 75014, Paris, France.
GHU-Paris Psychiatrie et Neurosciences, Hôpital Sainte Anne, F-75014, Paris, France.

Chun-Lei Zhang (CL)

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

Laetitia Cobret (L)

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

Alexander Gast (A)

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

Severine Morisset-Lopez (S)

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

Rebecca Piskorowski (R)

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

Dominique Langui (D)

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

Joachim Jose (J)

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

Guillaume Chevreux (G)

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

Heike Rebholz (H)

Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Laboratory of Signaling mechanisms in neurological disorders, 75014, Paris, France. heike.rebholz@inserm.fr.
GHU-Paris Psychiatrie et Neurosciences, Hôpital Sainte Anne, F-75014, Paris, France. heike.rebholz@inserm.fr.
Center of Neurodegeneration, Faculty of Medicine, Danube Private University, Krems, Austria. heike.rebholz@inserm.fr.

Classifications MeSH