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CASK is involved in transcription control, in the regulation of trafficking of the post\u2010synaptic NMDA and \u03b1\u2010amino\u20103\u2010hydroxy\u20105\u2010methyl\u20104\u2010isoxazolepropionic acid receptors, and acts as a presynaptic scaffolding protein. For <jats:italic>CASK<\/jats:italic> missense mutations, it is mostly unclear which of CASK\u2019s molecular interactions and cellular functions are altered and contribute to patient phenotypes. We identified five <jats:italic>CASK<\/jats:italic> missense mutations in male patients affected by neurodevelopmental disorders. These and five previously reported mutations were systematically analysed with respect to interaction with CASK interaction partners by co\u2010expression and co\u2010immunoprecipitation. We show that one mutation in the L27 domain interferes with binding to synapse\u2010associated protein of 97\u00a0kDa. Two mutations in the guanylate kinase (GK) domain affect binding of CASK to the nuclear factors CASK\u2010interacting nucleosome assembly protein (CINAP) and T\u2010box, brain, 1 (Tbr1). A total of five mutations in GK as well as PSD\u201095\/discs large\/ZO\u20101 (PDZ) domains affect binding of CASK to the pre\u2010synaptic cell adhesion molecule Neurexin. Upon expression in neurons, we observe that binding to Neurexin is not required for pre\u2010synaptic 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\u2010induced 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.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15215-fig-0010-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15215","type":"journal-article","created":{"date-parts":[[2020,10,14]],"date-time":"2020-10-14T18:17:23Z","timestamp":1602699443000},"page":"1331-1350","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Missense mutations in <i>CASK,<\/i> coding for the calcium\u2010\/calmodulin\u2010dependent serine protein kinase, interfere with neurexin binding and neurexin\u2010induced oligomerization"],"prefix":"10.1111","volume":"157","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6995-7239","authenticated-orcid":false,"given":"Yingzhou Edward","family":"Pan","sequence":"first","affiliation":[{"name":"Institute for Human Genetics University Medical Center Hamburg\u2010Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debora","family":"Tibbe","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics University Medical Center Hamburg\u2010Eppendorf Hamburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederike Leonie","family":"Harms","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics University Medical Center Hamburg\u2010Eppendorf Hamburg 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