Cerebellar hypoplasia caused by calcium/calmodulin-dependent serine protein kinase deficiency.

Calcium/calmodulin-dependent serine protein kinase (CASK) is an X-linked multidomain scaffolding protein originally identified as an intracellular binding partner for Neurexins, a family of presynaptic cell-adhesion molecules. Loss-of-function mutations in CASK cause microcephaly with pontine and cerebellar hypoplasia (MICPCH), a severe neurodevelopmental disorder predominantly affecting females. Although CASK has been implicated in synaptic organization and transcriptional regulation, the mechanisms underlying the cerebellar hypoplasia have remained unsolved. Recent studies using genetically engineered mouse models and cerebellar granule cell cultures suggest that CASK is essential for neuronal survival rather than for initial patterning in the cerebellum. These works further reveal that X-chromosome inactivation-driven mosaicism influences the pathology of this disorder and that CASK deficiency activates c-Jun N-terminal kinase (JNK) signaling. In this review, we integrate these findings with the synaptic cell-adhesion biology, in relevance to Neurexin-CASK interaction and role of CASK in cerebellar neuron survival and discuss emerging therapeutic implications for CASK-related disorders.