A novel &lt;i&gt;CASK&lt;/i&gt; mutation identified in siblings exhibiting developmental disorders with/without microcephaly

Seto, Toshiyuki; Hamazaki, Takashi; Nishigaki, Satsuki; Kudo, Satoshi; Shintaku, Haruo; Ondo, Yumiko; Shimojima, Keiko; Yamamoto, Toshiyuki

doi:10.5582/irdr.2017.01031

Cited by 21 publications

(24 citation statements)

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“…The stability of XCI during iPSC reprogramming varies between protocols, and activation of both X chromosomes with subsequent random silencing of one X has been observed 75 . The milder phenotype in females carrying CASK mutations with skewed XCI suggests that the proportion of CASK-deficient cells is crucial for phenotype severity 5,8 . The escape of CASK WT in the MICPCH CASK_dup4/5 cells likely rescues the cellular phenotype in our in vitro model, and we were unable to capture all pathoetiological mechanisms in the case with MICPCH.…”

Section: Discussionmentioning

confidence: 99%

Presynaptic dysfunction in CASK-related neurodevelopmental disorders

et al. 2020

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CASK-related disorders are genetically defined neurodevelopmental syndromes. There is limited information about the effects of CASK mutations in human neurons. Therefore, we sought to delineate CASK-mutation consequences and neuronal effects using induced pluripotent stem cell-derived neurons from two mutation carriers. One male case with autism spectrum disorder carried a novel splice-site mutation and a female case with intellectual disability carried an intragenic tandem duplication. We show reduction of CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of genes involved in presynaptic development and of CASK protein interactors. Furthermore, CASK-deficient neurons showed decreased inhibitory presynapse size as indicated by VGAT staining, which may alter the excitatory–inhibitory (E/I) balance in developing neural circuitries. Using in vivo magnetic resonance spectroscopy quantification of GABA in the male mutation carrier, we further highlight the possibility to validate in vitro cellular data in the brain. Our data show that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders.

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Section: Discussionmentioning

confidence: 99%

Presynaptic dysfunction in CASK-related neurodevelopmental disorders

et al. 2020

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“…For CASK-related disorders, there has been no systematic evaluation of behavioral phenotypes. In two multiplex families, the affected individuals were described as having "autistic" or "obsessive" behaviors (Hackett et al, 2010;Seto et al, 2017). In one study of de novo CASK mutations, motor stereotypies were noted in about half of the children (Burglen et al, 2012).…”

Section: Connecting Excessive Repetitive Grooming To Human Phenotypesmentioning

confidence: 99%

Spontaneous motor-behavior abnormalities in twoDrosophilamodels of neurodevelopmental disorders

Andrew

Moe

Chen

et al. 2020

Journal of Neurogenetics

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“…The stability of XCI during iPSC re-programing varies between protocols, and activation of both X chromosomes with subsequent random silencing of one X has been observed (Dandulakis et al, 2016). The milder phenotype in females carrying CASK mutations with skewed XCI suggests that the proportion of CASK-deficient cells is crucial for phenotype severity (Moog et al, 2011;Seto et al, 2017). Thus, the escape of CASKWT in the MICPCHCASK_dup4/5 cells is unlikely to recapitulate all pathoetiological mechanisms in cases with MICPCH.…”

Section: Cask-related Disorders Have Emerged As An Important Genetic mentioning

confidence: 99%

“…The majority of cases reported with CASK-related disorders are females with MICPCH, caused by heterozygous loss-of-function (LoF) variants (Burglen et al, 2012;Hayashi et al, 2017;Moog et al, 2011;Najm et al, 2008). Skewed X-chromosome inactivation (XCI) has shown protective effects against more severe phenotypes (Moog et al, 2011;Seto et al, 2017). Missense variants, found both in females and males cause microcephaly, XL-ID, DD or ASD (Cristofoli et al, 2018;Deciphering Developmental Disorders, 2017;Gupta et al, 2014;Hackett et al, 2010;Iossifov et al, 2014;LaConte et al, 2018;Moog et al, 2015;Piluso et al, 2009;Sanders et al, 2012;Seto et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Skewed X-chromosome inactivation (XCI) has shown protective effects against more severe phenotypes (Moog et al, 2011;Seto et al, 2017). Missense variants, found both in females and males cause microcephaly, XL-ID, DD or ASD (Cristofoli et al, 2018;Deciphering Developmental Disorders, 2017;Gupta et al, 2014;Hackett et al, 2010;Iossifov et al, 2014;LaConte et al, 2018;Moog et al, 2015;Piluso et al, 2009;Sanders et al, 2012;Seto et al, 2017). The molecular pathways and cellular phenotypes associated with genetic variants causing CASK-related disorders are mostly unknown, especially in human neurons.…”

Section: Introductionmentioning

confidence: 99%

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Presynaptic dysfunction inCASK-related neurodevelopmental disorders

Becker

Mastropasqua

Reising

et al. 2019

Preprint

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HighlightsModelling of CASK-related disorders using iPSC-derived human neuronal cells CASK mutations cause dysregulation of its protein interactor partners Reduced CASK levels primarily affect inhibitory presynapse development In vitro GABAergic phenotype predicts in vivo neurotransmitter levels Summary (150 words)CASK-related disorders are a genetically defined group of neurodevelopmental syndromes.There is limited information about the effects of CASK mutations in human neurons. Therefore, we sought to delineate CASK mutation consequences and neuronal level effects using induced pluripotent stem cell-derived neurons from two mutation carriers; one male diagnosed with ASD and a female with MICPCH. We show a reduction of the CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of gene sets involved in presynaptic development and CASK protein interactors. Furthermore, CASKdeficient neurons showed decreased inhibitory presynapse size as indicated by VGAT staining, which may alter the excitatory-inhibitory (E/I) balance in developing neural circuitries. Using in vivo magnetic resonance spectroscopy quantification of GABA in the male mutation carrier, we further highlight the possibility to validate in vitro cellular data in brain. Our data shows that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders.

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A novel <i>CASK</i> mutation identified in siblings exhibiting developmental disorders with/without microcephaly

Cited by 21 publications

References 20 publications

Presynaptic dysfunction in CASK-related neurodevelopmental disorders

Presynaptic dysfunction in CASK-related neurodevelopmental disorders

Spontaneous motor-behavior abnormalities in twoDrosophilamodels of neurodevelopmental disorders

Presynaptic dysfunction inCASK-related neurodevelopmental disorders

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