Biology:CASK

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Short description: Protein-coding gene in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Peripheral plasma membrane protein CASK is a protein that in humans is encoded by the CASK gene.[1][2] This gene is also known by several other names: CMG 2 (CAMGUK protein 2), calcium/calmodulin-dependent serine protein kinase 3 and membrane-associated guanylate kinase 2. CASK gene mutations are the cause of XL-ID with or without nystagmus and MICPCH, an X-linked neurological disorder.

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 mental retardation,[3] including specifically mental retardation and microcephaly with pontine and cerebellar hypoplasia.[4] 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.[5] 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.[6]

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[7][8] 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.[8]

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.[9]

The exact mode of pathology is not clear, but evidence from mice models indicates CASK deficiency in neurones causes the following effects:[10]

  • reduced levels of associated proteins such as Mint1[11] 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[12]
  • Down-regulation of GluN2B resulting in disruption of synaptic E/I balance[13]

Even slight changes in CASK expression in humans leads to dysregulation of the formation of presynapses, especially in inhibitory neurones.[6]

Interactions

CASK has been shown to interact with:

External links

References

  1. ↑ "The location of human CASK at Xp11.4 identifies this gene as a candidate for X-linked optic atrophy". Genomics 51 (2): 308–309. July 1998. doi:10.1006/geno.1998.5404. PMID 9722958. 
  2. ↑ "Entrez Gene: CASK Calcium/calmodulin-dependent serine protein kinase (MAGUK family)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8573. 
  3. ↑ "A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation". Nature Genetics 41 (5): 535–543. May 2009. doi:10.1038/ng.367. PMID 19377476. 
  4. ↑ "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 7 (18): 18. March 2012. doi:10.1186/1750-1172-7-18. PMID 22452838. 
  5. ↑ "CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes". European Journal of Human Genetics 18 (5): 544–552. May 2010. doi:10.1038/ejhg.2009.220. PMID 20029458. 
  6. ↑ 6.0 6.1 "Presynaptic dysfunction in CASK-related neurodevelopmental disorders". Translational Psychiatry 10 (1): 312. September 2020. doi:10.1038/s41398-020-00994-0. PMID 32929080. 
  7. ↑ "Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum". Nature Genetics 40 (9): 1065–1067. September 2008. doi:10.1038/ng.194. PMID 19165920. 
  8. ↑ 8.0 8.1 "Phenotypic and molecular insights into CASK-related disorders in males". Orphanet Journal of Rare Diseases 10 (1): 44. April 2015. doi:10.1186/s13023-015-0256-3. PMID 25886057. 
  9. ↑ "Expanding the natural history of CASK-related disorders to the prenatal period". Developmental Medicine and Child Neurology 65 (4): 544–550. September 2022. doi:10.1111/dmcn.15419. PMID 36175354. 
  10. ↑ "Deletion of CASK in mice is lethal and impairs synaptic function". Proceedings of the National Academy of Sciences of the United States of America 104 (7): 2525–2530. February 2007. doi:10.1073/pnas.0611003104. PMID 17287346. Bibcode: 2007PNAS..104.2525A. 
  11. ↑ "A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain" (in English). Cell 94 (6): 773–782. September 1998. doi:10.1016/S0092-8674(00)81736-5. PMID 9753324. 
  12. ↑ "De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy". Nature Genetics 40 (6): 782–788. June 2008. doi:10.1038/ng.150. PMID 18469812. 
  13. ↑ "Deficiency of calcium/calmodulin-dependent serine protein kinase disrupts the excitatory-inhibitory balance of synapses by down-regulating GluN2B". Molecular Psychiatry 24 (7): 1079–1092. July 2019. doi:10.1038/s41380-018-0338-4. PMID 30610199. 
  14. ↑ 14.0 14.1 "Protein trafficking and anchoring complexes revealed by proteomic analysis of inward rectifier potassium channel (Kir2.x)-associated proteins". The Journal of Biological Chemistry 279 (21): 22331–22346. May 2004. doi:10.1074/jbc.M400285200. PMID 15024025. 
  15. ↑ 15.0 15.1 15.2 15.3 "A multiprotein trafficking complex composed of SAP97, CASK, Veli, and Mint1 is associated with inward rectifier Kir2 potassium channels". The Journal of Biological Chemistry 279 (18): 19051–19063. April 2004. doi:10.1074/jbc.M400284200. PMID 14960569. 
  16. ↑ 16.0 16.1 "Identification of an evolutionarily conserved heterotrimeric protein complex involved in protein targeting". The Journal of Biological Chemistry 273 (48): 31633–31636. November 1998. doi:10.1074/jbc.273.48.31633. PMID 9822620. 
  17. ↑ "Molecular analysis of the X11-mLin-2/CASK complex in brain". The Journal of Neuroscience 19 (4): 1307–1316. February 1999. doi:10.1523/JNEUROSCI.19-04-01307.1999. PMID 9952408. 
  18. ↑ "Interaction of the plasma membrane Ca2+ pump 4b/CI with the Ca2+/calmodulin-dependent membrane-associated kinase CASK". The Journal of Biological Chemistry 278 (11): 9778–9783. March 2003. doi:10.1074/jbc.M212507200. PMID 12511555. 
  19. ↑ "Transcriptional modification by a CASK-interacting nucleosome assembly protein". Neuron 42 (1): 113–128. April 2004. doi:10.1016/S0896-6273(04)00139-4. PMID 15066269. 
  20. ↑ 20.0 20.1 "Postsynaptic targeting of alternative postsynaptic density-95 isoforms by distinct mechanisms". The Journal of Neuroscience 22 (15): 6415–6425. August 2002. doi:10.1523/JNEUROSCI.22-15-06415.2002. PMID 12151521. 
  21. ↑ "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 275 (52): 41192–41200. December 2000. doi:10.1074/jbc.M002078200. PMID 10993877. 
  22. ↑ "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 276 (12): 9291–9296. March 2001. doi:10.1074/jbc.M006991200. PMID 11120739. 
  23. ↑ "Junctional adhesion molecule interacts with the PDZ domain-containing proteins AF-6 and ZO-1". The Journal of Biological Chemistry 275 (36): 27979–27988. September 2000. doi:10.1074/jbc.M002363200. PMID 10856295. 
  24. ↑ "CASK inhibits ECV304 cell growth and interacts with Id1". Biochemical and Biophysical Research Communications 328 (2): 517–521. March 2005. doi:10.1016/j.bbrc.2005.01.014. PMID 15694377. 
  25. ↑ "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 165 (3): 923–936. September 2004. doi:10.1016/S0002-9440(10)63354-8. PMID 15331416. 
  26. ↑ "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 277 (1): 486–491. January 2002. doi:10.1074/jbc.M109806200. PMID 11679592. 
  27. ↑ 27.0 27.1 "The scaffolding protein CASK mediates the interaction between rabphilin3a and beta-neurexins". FEBS Letters 497 (2–3): 99–102. May 2001. doi:10.1016/S0014-5793(01)02450-4. PMID 11377421. 
  28. ↑ "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 142 (1): 129–138. July 1998. doi:10.1083/jcb.142.1.129. PMID 9660868. 

Further reading

External links



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