What we know about CASK
- CASK gene mutations cause a number of diseases, including: ‘MICPCH’ and ‘XL-ID with or without nystagmus’.
- The CASK gene is ubiquitously expressed with high expression in the developing human brain.
- CASK is critical for extinction of associative memory.
- The CASK protein performs a selectively essential function without being in itself required for core activities of neurons, such as membrane excitability, Ca2+-triggered presynaptic release, or postsynaptic receptor functions.
- The CASK gene is not essential for formation of structurally normal synapses.
Which proteins does CASK interact with?
In the pre-synapse
CASK regulates the synaptic vesicle exocytosis and neuronal cell adhesion through a tripartite complex with VELI1 (LIN7A) and MINT1 (APBA1). In Knock Out mice, Mint and neurexin levels are lower.
CASK binds to neurexin (which binds to Neuroligin 1). As a result neuroligin levels are found to be higher in CASK mutant cells.
CASK contributes to the regulation of ionotropic receptor trafficking.
CASK appears to be a central protein that participates in trafficking and plasma membrane localization of Kir2 channels.
Which genes does CASK regulate?
Reduced CASK levels have been seen to affect the transcription of pre-synaptic genes
CASK directly interacts with NRXN1 – a gene associated with neurodevelopmental disorders. CASK gene mutations down-regulate NRXN1. Research has shown that the CASK–NRXN1 interaction is disrupted in MICPCH.
TBR1 is a causative gene for autism.
The binding of CASK to TBR1 in the nucleus facilitates the transcription of T-element-containing genes, such as Reelin and GluN2B (NMDA glutamate receptor subunit). In MICPCH, The resultant down-regulation of GluN2B probably causes disruption of synaptic E/I balance.
It has been found that mice with a CASK mutation have less CASK-TBR1 interaction and so MICPCH reduces the TBR1-GRIN2B pathway.