Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the CASK gene result in mental retardation and microcephaly in humans, suggesting an important role for CASK in brain. CASK gene knockout in mice causes neonatal lethality, making further elucidation in mouse models difficult. Because CASK was originally identified as a multidomain adaptor protein, identifying a point mutation interrupting a specific protein interaction would be useful in dissecting its molecular function. Here, a Thr-to-Ala mutation in the rat CASK guanylate kinase (GK) domain was shown to reduce interactions among CASK and Tbr-1 and CINAP, two critical brain proteins. The effect is specific: this mutation does not affect CASK dimerization that occurs via the GK domain. The Tbr-1-CASK-CINAP complex regulates expression of the NMDA receptor subunit 2b (NR2b), and we show that this point mutation also affects NR2b promoter activity. The identification of this mutation may make it possible to further dissect the function of CASK in brain.
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PMID:CASK point mutation regulates protein-protein interactions and NR2b promoter activity. 1927 91

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.
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PMID:Missense mutations in CASK interfere with neurexin binding and neurexin-induced oligomerization. 3309 Apr 94