Understanding the causal developmental mechanisms underlying CASK-related neurodevelopmental disorders
CASK is a multidomain scaffolding protein belonging to the MAGUK (membrane-associated guanylate kinase) family, with critical roles in brain development and synaptic function. CASK interacts with a variety of protein partners that regulate diverse processes such as cortical lamination, dendritic outgrowth, and presynaptic neurotransmitter release. For example, CASK directly binds to neurexin-1 at synapses and to transcription factors such as Tbr1 to regulate gene expression relevant to synaptic signaling. These molecular interactions place CASK at the intersection of key pathways controlling brain structure and function.
The importance of CASK is underscored by the discovery of CASK loss-of-function (LoF) and pathogenic missense variants in individuals with neurodevelopmental disorders, including microcephaly with pontine and cerebellar hypoplasia (MICPCH), X-linked intellectual disability (XLID), autism spectrum disorders, and epilepsy. CASK mutations show sex-specific patterns: heterozygous LoF variants in females often lead to severe outcomes, while hemizygous LoF in males is typically lethal. Males more commonly present with pathogenic missense variants, contributing to a broad spectrum of clinical features. Despite its clear genetic link to human disease, the molecular and cellular consequences of CASK mutations in human neural development remain poorly understood.
In the Pak Lab, we take a stem cell–based and clinically informed approach to address this knowledge gap. We generate CASK LoF mutations using CRISPR/Cas9 gene editing in control iPSCs and reprogram iPSCs from individuals carrying defined CASK missense variants. Through these models, our recent work has uncovered a novel link between CASK and the WNT/β-catenin signaling pathway (McSweeney et al., 2022). Unpublished and ongoing work revealed an unexpected role for CASK in early neural progenitor cell fate specification, particularly within cerebellar organoids. Building on these findings, we are actively exploring brain region–specific 3D models to study the causal mechanisms underlying cerebellar hypoplasia and related developmental deficits observed in CASK-related syndromes with the hopes to deliver personalized therapeutics to patients.
See publications related to this research focus:
McSweeney et al., 2022 iScience