Investigating the Mechanism of Optic Nerve Hypoplasia Associated with CASK Mutation

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 DESCRIPTION (provided by applicant): Optic nerve hypoplasia (ONH) is one of the most common congenital optic disc disorders and is an increasingly prevalent cause of childhood blindness. In addition to being considered a pervasive developmental defect, an association between ONH and autism spectrum disorder (ASD) has been established. Despite its prevalence, the molecular and cellular mechanisms leading to ONH is not clear. ONH is most studied in the context of septo-optic dysplasia which is associated with absent septum pellucidum and midline defects. Here, we identified a novel mouse model of ONH and propose to use it to elucidate mechanisms that lead to phenotypes associated with the disease. Specifically, we discovered ONH in mice with reduced levels of CASK. Human mutations in CASK lead to X-linked mental retardation with some of the patients falling within ASD phenotype. Affected patients often present with ponto-cerebellar hypoplasia and optic nerve hypoplasia/atrophy. CASK is a specific kinase for synaptic adhesion molecule neurexin, mutations in neurexin and its trans-synaptic interacting partner neuroligin also are associated with ASD. Thus investigating CASK mutation as a model of ONH has the potential to provide molecular link between ASD and ONH. Our preliminary data indicate that CASK heterozygous knockout mice (+/-) exhibit a thinner optic nerve with axonal loss and signs of astrogliosis. We will use animal genetics, developmental and imaging studies to understand pathogenesis of ONH in these mice. Specifically we will analyze whether the axonal loss are primary or secondary in nature, the cell autonomous effect of CASK loss during and after development of optic nerve and the precise cellular pathology that is associated with ONH. Our proposal has the potential to uncover a molecular link between ASD and ONH.