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Pan, Y.E. and Tibbe, D. and Harms, F.L. and Reißner, C. and Becker, K. and Dingmann, B. and Mirzaa, G. and Kattentidt‐Mouravieva, A.A. and Shoukier, M. and Aggarwal, Shagun and Missler, M. and Kutsche, K. and Kreienkamp, H.J. (2020) Missense mutations in CASK, coding for the calcium‐/calmodulin‐dependent serine protein kinase, interfere with neurexin binding and neurexin‐induced oligomerization. Journal of Neurochemistry. ISSN 0022-3042 (In Press)

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Mutations in the X-linked gene coding for the calcium-/calmodulin dependent serine protein kinase (CASK) are associated with severe neurological disorders ranging from intellectual disability (in males) to mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH). CASK is involved in transcription control, in the regulation of trafficking of the postsynaptic NMDA and AMPA receptors, and acts as a presynaptic scaffolding protein. For CASK missense mutations it is mostly unclear which of CASK's molecular interactions and cellular functions are altered and contribute to patient phenotypes. We identified five CASK missense mutations in male patients affected by neurodevelopmental disorders. These and five previously reported mutations were systematically analyzed with respect to interaction with CASK interaction partners by coexpression and coimmunoprecipitation. We show that one mutation in the L27 domain interferes with binding to Sap97. Two mutations in the guanylate kinase (GK) domain affect binding of CASK to the nuclear factors CINAP and Tbr1. A total of five mutations in GK as well as PDZ domains affect binding of CASK to the presynaptic cell adhesion molecule Neurexin. Upon expression in neurons, we observe that binding to Neurexin is not required for presynaptic localization of CASK. We show by bimolecular fluorescence complementation assay that Neurexin induces oligomerization of CASK, and that mutations in GK and PDZ domains interfere with the Neurexin-induced oligomerization of CASK. Our data are supported by molecular modelling, where we observe that the cooperative activity of PDZ, SH3 and GK domains is required for Neurexin binding and oligomerization of CASK.

Item Type: Article
Subjects: Genetics
Depositing User: Dr P. Divakar
Date Deposited: 10 Nov 2020 18:12
Last Modified: 10 Nov 2020 18:12
URI: http://cdfd.sciencecentral.in/id/eprint/981

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