Calcium/calmodulin-dependent serine protein kinase (CASK), a protein implicated in mental retardation and autism-spectrum disorders, interacts with T-Brain-1 (TBR1) to control extinction of associative memory in male mice

Huang, Tzyy-Nan; Hsueh, Yi‐Ping

doi:10.1503/jpn.150359

Cited by 23 publications

(20 citation statements)

References 43 publications

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“…Indeed, we detected TBR1 immunoreactivity mostly in the layer 2/3 neurons of P14 mice (Supplementary Figure 8). To examine whether the synaptic phenotype of CASK-deficient neurons was related to the CASK/TBR1 interaction, we co-transfected them with CASK containing a T704A mutation, which interferes with CASK’s binding to TBR1, in the CASK-KD neurons and analyzed mPSCs [43–45]. Like the CASK ΔG mutant, the CASK-T704A mutant failed to rescue the aberrant frequencies of mEPSCs and mIPSCs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Deficiency of calcium/calmodulin-dependent serine protein kinase disrupts the excitatory-inhibitory balance of synapses by down-regulating GluN2B

Kasem¹

2019

Mol Psychiatry

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Calcium/calmodulin-dependent serine protein kinase (CASK) is a membrane-associated guanylate kinase (MAGUK) protein that is associated with neurodevelopmental disorders. CASK is thought to have both pre- and postsynaptic functions, but the mechanism and consequences of its functions in the brain have yet to be elucidated, because homozygous CASK-knockout (CASK-KO) mice die before brain maturation. Taking advantage of the X-chromosome inactivation (XCI) mechanism, here we examined the synaptic functions of CASK-KO neurons in acute brain slices of heterozygous CASK-KO female mice. We also analyzed CASK-knockdown (KD) neurons in acute brain slices generated by in utero electroporation. Both CASK-KO and CASK-KD neurons showed a disruption of the excitatory and inhibitory (E/I) balance. We further found that the expression level of the N-methyl-d-aspartate receptor subunit GluN2B was decreased in CASK-KD neurons and that overexpressing GluN2B rescued the disrupted E/I balance in CASK-KD neurons. These results suggest that the down-regulation of GluN2B may be involved in the mechanism of the disruption of synaptic E/I balance in CASK-deficient neurons.

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Section: Resultsmentioning

confidence: 99%

Deficiency of calcium/calmodulin-dependent serine protein kinase disrupts the excitatory-inhibitory balance of synapses by down-regulating GluN2B

Kasem¹

2019

Mol Psychiatry

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“…For example, CASK’s SH3 domain is also proposed to interact with the polyproline tracts of other proteins such as the alpha subunit of a neuronal calcium channel (Maximov et al 1999), and the GuK domain of CASK may interact with the transcription factor TBR1 (Hsueh et al 2000). It is unlikely, however, that the interruption of any of these interactions causes the microcephaly seen here, since the deletion of CASK does not affect the functioning of presynaptic calcium channels (Atasoy et al 2007), and the disruption of the CASK-TBR1 interaction in mouse does not produce microcephaly (Huang and Hsueh 2017). In fact, nuclear translocation of GFP-CASK with TBR1 was not observed even for wildtype CASK (Figure 4), further weakening the hypothesis that the CASK-TBR-1 interaction is responsible for the microcephaly component of CASK-related phenotypes.…”

Section: Discussionmentioning

confidence: 85%

Two microcephaly-associated novel missense mutations in CASK specifically disrupt the CASK–neurexin interaction

et al. 2018

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Deletion and truncation mutations in the X-linked gene CASK are associated with severe intellectual disability (ID), microcephaly and pontine and cerebellar hypoplasia in girls (MICPCH). The molecular origin of CASK-linked MICPCH is presumed to be due to disruption of the CASK-Tbr-1 interaction. This hypothesis, however, has not been directly tested. Missense variants in CASK are typically asymptomatic in girls. We report three severely affected girls with heterozygous CASK missense mutations (M519T (2), G659D (1)) who exhibit ID, microcephaly, and hindbrain hypoplasia. The mutation M519T results in the replacement of an evolutionarily invariant methionine located in the PDZ signaling domain known to be critical for the CASK-neurexin interaction. CASK is incapable of binding to neurexin, suggesting a critically important role for the CASK-neurexin interaction. The mutation G659D is in the SH3 (Src homology 3) domain of CASK, replacing a semi-conserved glycine with aspartate. We demonstrate that the CASK mutation affects the CASK protein in two independent ways: (1) it increases the protein's propensity to aggregate; and (2) it disrupts the interface between CASK's PDZ (PSD95, Dlg, ZO-1) and SH3 domains, inhibiting the CASK-neurexin interaction despite residing outside of the domain deemed critical for neurexin interaction. Since heterozygosity of other aggregation-inducing mutations (e.g., CASK) does not produce MICPCH, we suggest that the G659D mutation produces microcephaly by disrupting the CASK-neurexin interaction. Our results suggest that disruption of the CASK-neurexin interaction, not the CASK-Tbr-1 interaction, produces microcephaly and cerebellar hypoplasia. These findings underscore the importance of functional validation for variant classification.

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“…Behavioral assays were conducted blind. No statistical method was applied to evaluate the sample size, but our sample sizes are similar to previous publications (Huang et al, 2014;Huang and Hsueh, 2017). Data meet the assumption of the tests, e.g., normal distribution.…”

Section: Quantification and Statistical Analysismentioning

confidence: 94%

Interhemispheric Connectivity Potentiates the Basolateral Amygdalae and Regulates Social Interaction and Memory

et al. 2019

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Calcium/calmodulin-dependent serine protein kinase (CASK), a protein implicated in mental retardation and autism-spectrum disorders, interacts with T-Brain-1 (TBR1) to control extinction of associative memory in male mice

Cited by 23 publications

References 43 publications

Deficiency of calcium/calmodulin-dependent serine protein kinase disrupts the excitatory-inhibitory balance of synapses by down-regulating GluN2B

Deficiency of calcium/calmodulin-dependent serine protein kinase disrupts the excitatory-inhibitory balance of synapses by down-regulating GluN2B

Two microcephaly-associated novel missense mutations in CASK specifically disrupt the CASK–neurexin interaction

Interhemispheric Connectivity Potentiates the Basolateral Amygdalae and Regulates Social Interaction and Memory

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