CASK

Peripheral plasma membrane protein CASK is a protein that in humans is encoded by the CASK gene.^[5][6] 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

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[11]^[12] 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.^[12]

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.^[13]

The exact mode of pathology is not clear, but evidence from mice models indicates CASK deficiency in neurones causes the following effects:^[14]

• reduced levels of associated proteins such as Mint1^[15] and neurexin
• Higher levels of Neuroligin 1
• Increased
  GABA release affecting the E/I balance in maturing neural circuits^[16]
• Down-regulation of GluN2B resulting in disruption of synaptic E/I balance[17]

Even slight changes in CASK expression in humans leads to dysregulation of the formation of presynapses, especially in inhibitory neurones.^[10]

Interactions

CASK has been shown to

• KCNJ4^[18][19]
• APBA1^[20][21]
• ATP2B4^[22]
• CINAP and TBR1^[23]
• DLG1^[19][24][25]
• DLG4^[24]
• F11 receptor^[26][27]
• ID1^[28]
• KCNJ12^[18][19]
• LIN7A^[19][20]
• Nephrin^[29]
• Parkin (ligase)^[30]
• RPH3A^[31]
• SDC2^[31][32]

• CASK Research Foundation - A non-profit based in the UK for research, information and support into CASK related disorders including MICPCH
• Angelina CASK Neurological Research Foundation - A non-profit based in Australia creating research grants for research into CASK gene related disorders.

References