Complete Loss of CASK Causes Severe Ataxia Through Cerebellar Degeneration

Abstract Heterozygous loss of X-linked genes like CASK and MeCP2 (Rett syndrome) causes neurodevelopmental disorders (NDD) in girls, while in boys loss of the only allele of these genes leads to profound encephalopathy. The cellular basis for these disorders remains unknown. CASK is presumed to work through the Tbr1-reelin pathway in neuronal migration. Here we report clinical and histopathological analysis of a deceased 2-month-old boy with a CASK-null mutation. Although smaller in size, the CASK-null human brain exhibits normal lamination without defective neuronal differentiation, migration, or axonal guidance, excluding the role of reelin. The hypoplastic cerebellum instead displayed astrogliosis, a marker for neuronal loss. We therefore hypothesized that cerebellar hypoplasia with CASK loss is a result of early neurodegeneration. We generated a mouse line where CASK is completely deleted (hemizygous and homozygous) from post-migratory neurons in the cerebellum. Data confirm that a small cerebellum in CASK-loss results from post-developmental degeneration of cerebellar granule neurons. We further demonstrate that at least in cerebellum the functional loss with CASK deletion results secondary to degeneration of granule cells rather that any acute molecular functional loss of CASK. Intriguingly, female mice with heterozygous deletion of CASK in the cerebellum did not display any neurodegeneration. We suggest that NDDs like CASK mutation and Rett syndrome are pathologically neurodegenerative; however, random X-chromosome inactivation in the heterozygous mutant girls results in 50% of cells expressing the functional gene, resulting in a non-progressive pathology, whereas complete loss of the only allele in boys leads to unconstrained degeneration and encephalopathy.