Complete loss of the X-linked gene CASK causes severe cerebellar degeneration

X-linked disorders like CASK-linked pontocerebellar hypoplasia and Rett syndrome, predominantly affecting girls, are presumed to be neurodevelopmental disorders. Here, by performing a detailed analysis of a boy without CASK and genetically ablating CASK from cerebellar neurons in mice, we demonstrate that CASK loss does not affect neuronal or brain development. Instead, CASK loss results in neuronal degeneration leading to cerebellar hypoplasia. We propose that X-linked disorders (like CASK mutation) previously assumed to be neurodevelopmental are actually neurodegenerative conditions. In girls with heterozygous mutation, random X-chromosome inactivation allows 50% of brain cells to express CASK, which disrupts the progression of neurodegeneration. (By Dr. Konark Mukherjee, https://jmg.bmj.com/content/early/2022/02/10/jmedgenet-2021-108115 )

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