CASK

Gene

This gene is located on the short arm of the X chromosome (Xp11.4). It is 404,253 bases in length and lies on the Crick (minus) strand. The encoded protein has 926 amino acids with a predicted molecular weight of 105,123 daltons.

Function

This protein is a multidomain scaffolding protein with a role in synaptic transmembrane protein anchoring and ion channel trafficking. It interacts with the transcription factor TBR1 and binds to several cell-surface proteins including neurexins and syndecans.

Clinical importance

This gene has been implicated in X-linked intellectual disability, including specifically intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia. The role of CASK in disease is primarily associated with a loss of function (under expression) of the CASK gene as a result of a deletion, missense or splice mutation. It appears that mutations in the gene lead to diminished amounts of the protein being coded. As a result, CASK is unable to form complexes with other proteins leading to a cascade of events. Research has shown there is significant down-regulation of the genes involved in pre-synaptic development and of CASK protein interactors.

Males affected by CASK variants tend to have more severe symptoms than females due to the X-linked nature of the disease. These genetic issues are often fatal in the womb for male embryos or else lead to infant mortality. Females with CASK mutations have variable phenotypes with moderate to severe intellectual disability. CASK missense mutations and some splice mutations can lead to the milder neurodevelopmental phenotype.

CASK related disorders are mainly found in girls. The prevalence is unknown but generally thought to be below 400 cases worldwide. Patients are often born healthy but within the first few months of life show progressive microcephaly. Although there can be prenatal deceleration of head circumference growth, the majority of cases will not be diagnosed according to current recommendations for fetal CNS routine assessment.

The exact mode of pathology is not clear, but evidence from mice models indicates CASK deficiency in neurones causes the following effects:

• reduced levels of associated proteins such as Mint1 and neurexin
• Higher levels of Neuroligin 1
• Increased glutamate release at synapses and reduced GABA release affecting the E/I balance in maturing neural circuits
• Down-regulation of GluN2B resulting in disruption of synaptic E/I balance

Even slight changes in CASK expression in humans leads to dysregulation of the formation of presynapses, especially in inhibitory neurones.

Interactions

CASK has been shown to interact with:

• KCNJ4
• APBA1
• ATP2B4
• CINAP and TBR1
• DLG1
• DLG4
• F11 receptor
• ID1
• KCNJ12
• LIN7A
• Nephrin
• Parkin (ligase)
• RPH3A
• SDC2

References

References

1. (July 1998). "The location of human CASK at Xp11.4 identifies this gene as a candidate for X-linked optic atrophy". Genomics.
2. "Entrez Gene: CASK Calcium/calmodulin-dependent serine protein kinase (MAGUK family)".
3. (May 2009). "A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation". Nature Genetics.
4. (March 2012). "Spectrum of pontocerebellar hypoplasia in 13 girls and boys with CASK mutations: confirmation of a recognizable phenotype and first description of a male mosaic patient". Orphanet Journal of Rare Diseases.
5. (May 2010). "CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes". European Journal of Human Genetics.
6. (September 2020). "Presynaptic dysfunction in CASK-related neurodevelopmental disorders". Translational Psychiatry.
7. (September 2008). "Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum". Nature Genetics.
8. (April 2015). "Phenotypic and molecular insights into CASK-related disorders in males". Orphanet Journal of Rare Diseases.
9. (September 2022). "Expanding the natural history of CASK-related disorders to the prenatal period". Developmental Medicine and Child Neurology.
10. (February 2007). "Deletion of CASK in mice is lethal and impairs synaptic function". Proceedings of the National Academy of Sciences of the United States of America.
11. (September 1998). "A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain". Cell.
12. (June 2008). "De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy". Nature Genetics.
13. (July 2019). "Deficiency of calcium/calmodulin-dependent serine protein kinase disrupts the excitatory-inhibitory balance of synapses by down-regulating GluN2B". Molecular Psychiatry.
14. (May 2004). "Protein trafficking and anchoring complexes revealed by proteomic analysis of inward rectifier potassium channel (Kir2.x)-associated proteins". The Journal of Biological Chemistry.
15. (April 2004). "A multiprotein trafficking complex composed of SAP97, CASK, Veli, and Mint1 is associated with inward rectifier Kir2 potassium channels". The Journal of Biological Chemistry.
16. (February 1999). "Molecular analysis of the X11-mLin-2/CASK complex in brain". The Journal of Neuroscience.
17. (March 2003). "Interaction of the plasma membrane Ca2+ pump 4b/CI with the Ca2+/calmodulin-dependent membrane-associated kinase CASK". The Journal of Biological Chemistry.
18. (April 2004). "Transcriptional modification by a CASK-interacting nucleosome assembly protein". Neuron.
19. (December 2000). "hCASK and hDlg associate in epithelia, and their src homology 3 and guanylate kinase domains participate in both intramolecular and intermolecular interactions". The Journal of Biological Chemistry.
20. (August 2002). "Postsynaptic targeting of alternative postsynaptic density-95 isoforms by distinct mechanisms". The Journal of Neuroscience.
21. (March 2001). "Association of junctional adhesion molecule with calcium/calmodulin-dependent serine protein kinase (CASK/LIN-2) in human epithelial caco-2 cells". The Journal of Biological Chemistry.
22. (September 2000). "Junctional adhesion molecule interacts with the PDZ domain-containing proteins AF-6 and ZO-1". The Journal of Biological Chemistry.
23. (March 2005). "CASK inhibits ECV304 cell growth and interacts with Id1". Biochemical and Biophysical Research Communications.
24. (September 2004). "Nephrin forms a complex with adherens junction proteins and CASK in podocytes and in Madin-Darby canine kidney cells expressing nephrin". The American Journal of Pathology.
25. (January 2002). "Parkin and CASK/LIN-2 associate via a PDZ-mediated interaction and are co-localized in lipid rafts and postsynaptic densities in brain". The Journal of Biological Chemistry.
26. (May 2001). "The scaffolding protein CASK mediates the interaction between rabphilin3a and beta-neurexins". FEBS Letters.
27. (July 1998). "Human CASK/LIN-2 binds syndecan-2 and protein 4.1 and localizes to the basolateral membrane of epithelial cells". The Journal of Cell Biology.