Regulation of Liprin-α phase separation by CASK is disrupted by a mutation in its CaM kinase domain

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• CASK, a membrane-associated guanylate kinase (MAGUK), possesses a unique Ca2+/calmodulin-dependent kinase (CaMK) domain.
• This study investigates the role of CASK in neurodevelopmental disorders.

Observation:

• Four male patients with severe neurodevelopmental disorder and microcephaly were identified, all carrying missense variants in the CASK CaMK domain.
• One patient with the p.E115K variant exhibited microcephaly, pontocerebellar hypoplasia (PCH), and early death, presenting the MICPCH phenotype.
• All identified variants weakened the interaction between CASK and Liprin-α2, a presynaptic active zone protein.

Findings:

• Liprin-α proteins naturally form spherical phase-separated condensates, observed in HEK293T cells and primary neurons.
• CASK normally reverses Liprin-α2 condensate formation, a process linked to altered Liprin-α2 phosphorylation.
• The p.E115K variant did not interfere with Liprin-α2 condensate formation, unlike other pathogenic variants.

Implications:

• The regulation of Liprin-α2 phase condensate formation by CASK represents a newly identified function.
• Disruption of this CASK function is implicated in the pathogenesis of microcephaly with pontocerebellar hypoplasia (MICPCH).
• Maintaining CASK's role in regulating Liprin-α2 condensates is crucial for preventing PCH and associated neurodevelopmental disorders.