Najm J, Horn D, Wimplinger I, Golden JA, Chizhikov VV, Sudi J et al. Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum. Nat Genet 40: 1065-1067

Institut für Humangenetik, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany.
Nature Genetics (Impact Factor: 29.35). 10/2008; 40(9):1065-7. DOI: 10.1038/ng.194
Source: PubMed


CASK is a multi-domain scaffolding protein that interacts with the transcription factor TBR1 and regulates expression of genes involved in cortical development such as RELN. Here we describe a previously unreported X-linked brain malformation syndrome caused by mutations of CASK. All five affected individuals with CASK mutations had congenital or postnatal microcephaly, disproportionate brainstem and cerebellar hypoplasia, and severe mental retardation.

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    • "Our previous studies showed that TBR1 interacts with CASK (calcium/calmodulin-dependent serine protein kinase; Hsueh et al., 2000; Hsueh, 2009). Mutations in the CASK gene result in X-linked mental retardation (Najm et al., 2008; Tarpey et al., 2009; Moog et al., 2011). The CASK-TBR1 protein complex regulates the expression of glutamate receptor, ionotropic, N-methyl-D-aspartate 2B (Grin2b, also known as Nmdar2b; Wang et al., 2004a,b), which is critical for learning and memory and involved in autism and schizophrenia (Kristiansen et al., 2010; O’Roak et al., 2012b). "
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    ABSTRACT: The activity-regulated gene expression of transcription factors is required for neural plasticity and function in response to neuronal stimulation. T-brain-1 (TBR1), a critical neuron-specific transcription factor for forebrain development, has been recognized as a high-confidence risk gene for autism spectrum disorders (ASDs). Here, we show that in addition to its role in brain development, Tbr1 responds to neuronal activation and further modulates the Grin2b expression in adult brains and mature neurons. The expression levels of Tbr1 were investigated using both immunostaining and quantitative RT-PCR analyses. We found that the mRNA and protein expression levels of Tbr1 are induced by excitatory synaptic transmission driven by bicuculline or glutamate treatment in cultured mature neurons. The upregulation of Tbr1 expression requires the activation of both AMPA and NMDA receptors. Furthermore, behavioral training triggers Tbr1 induction in the adult mouse brain. The elevation of Tbr1 expression is associated with Grin2b upregulation in both mature neurons and adult brains. Using Tbr1-deficient neurons, we further demonstrated that TBR1 is required for the induction of Grin2b upon neuronal activation. Taken together with the previous studies showing that TBR1 binds the Grin2b promoter and controls expression of luciferase reporter driven by Grin2b promoter, the evidence suggests that TBR1 directly controls Grin2b expression in mature neurons. We also found that the addition of the calcium-calmodulin kinase II (CaMKII) antagonist KN-93, but not the calcium-dependent phosphatase calcineurin antagonist cyclosporin A, to cultured mature neurons noticeably inhibited Tbr1 induction, indicating that neuronal activation upregulates Tbr1 expression in a CaMKII-dependent manner. In conclusion, our study suggests that Tbr1 plays an important role in adult mouse brains in response to neuronal activation to modulate the activity-regulated gene transcription required for neural p
    Frontiers in Cellular Neuroscience 09/2014; 8:280. DOI:10.3389/fncel.2014.00280 · 4.29 Impact Factor
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    • "CASK‐related PCH CASK is on chromosome Xp11 . 4 ( OMIM 300749 ) and encodes a multi‐ domain scaffolding protein that interacts with TBR1 and regulates expression of genes involved in cortical development such as RELN [ Najm et al . , 2008 ] . CASK mutations occur de novo and more commonly affect females , pre - sumably because they are lethal in males ."
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    ABSTRACT: Cerebellar hypoplasia (CH) refers to a cerebellum with a reduced volume, and is a common, but non-specific neuroimaging finding. The etiological spectrum of CH is wide and includes both primary (malformative) and secondary (disruptive) conditions. Primary conditions include chromosomal aberrations (e.g., trisomy 13 and 18), metabolic disorders (e.g., molybdenum cofactor deficiency, Smith-Lemli-Opitz syndrome, and adenylosuccinase deficiency), genetic syndromes (e.g., Ritscher-Schinzel, Joubert, and CHARGE syndromes), and brain malformations (primary posterior fossa malformations e.g., Dandy-Walker malformation, pontine tegmental cap dysplasia and rhombencephalosynapsis, or global brain malformations such as tubulinopathies and α-dystroglycanopathies). Secondary (disruptive) conditions include prenatal infections (e.g., cytomegalovirus), exposure to teratogens, and extreme prematurity. The distinction between malformations and disruptions is important for pathogenesis and genetic counseling. Neuroimaging provides key information to categorize CH based on the pattern of involvement: unilateral CH, CH with mainly vermis involvement, global CH with involvement of both vermis and hemispheres, and pontocerebellar hypoplasia. The category of CH, associated neuroimaging findings and clinical features may suggest a specific disorder or help plan further investigations and interpret their results. Over the past decade, advances in neuroimaging and genetic testing have greatly improved clinical diagnosis, diagnostic testing, recurrence risk counseling, and information about prognosis for patients and their families. In the next decade, these advances will be translated into deeper understanding of these disorders and more specific treatments. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 06/2014; 166(2). DOI:10.1002/ajmg.c.31398 · 3.91 Impact Factor
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    • "Although CASK is ubiquitously expressed, its expression is strikingly high in the central nervous system, especially during development [5]. Mutations in CASK are associated with mental retardation as well as structural defects in the brain such as pontocerebellar hypoplasia, Ohtahara syndrome [6], FG syndrome with corpus callosum agenesis [6], [7], [8], [9], [10], tetralogy of Fallot [11], and autism spectrum disorders [12], [13]. "
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    ABSTRACT: The overwhelming amount of available genomic sequence variation information demands a streamlined approach to examine known pathogenic mutations of any given protein. Here we seek to outline a strategy to easily classify pathogenic missense mutations that cause protein misfolding and are thus good candidates for chaperone-based therapeutic strategies, using previously identified mutations in the gene CASK. We applied a battery of bioinformatics algorithms designed to predict potential impact on protein structure to five pathogenic missense mutations in the protein CASK that have been shown to underlie pathologies ranging from X-linked mental retardation to autism spectrum disorder. A successful classification of the mutations as damaging was not consistently achieved despite the known pathogenicity. In addition to the bioinformatics analyses, we performed molecular modeling and phylogenetic comparisons. Finally, we developed a simple high-throughput imaging assay to measure the misfolding propensity of the CASK mutants in situ. Our data suggests that a phylogenetic analysis may be a robust method for predicting structurally damaging mutations in CASK. Mutations in two evolutionarily invariant residues (Y728C and W919R) exhibited a strong propensity to misfold and form visible aggregates in the cytosolic milieu. The remaining mutations (R28L, Y268H, and P396S) showed no evidence of aggregation and maintained their interactions with known CASK binding partners liprin-α3 Mint-1, and Veli, indicating an intact structure. Intriguingly, the protein aggregation caused by the Y728C and W919R mutations was reversed by treating the cells with a chemical chaperone (glycerol), providing a possible therapeutic strategy for treating structural mutations in CASK in the future.
    PLoS ONE 02/2014; 9(2):e88276. DOI:10.1371/journal.pone.0088276 · 3.23 Impact Factor
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