CASK hypomorph mice display cone photoreceptor dysfunction

Abstract Variants in the X-linked gene CASK are associated with neurodevelopmental defects. Animal model studies have demonstrated that conditions such as cerebellar hypoplasia, microcephaly, and optic nerve hypoplasia (ONH) are related to loss-of-function (LOF) in the CASK gene. CASK variants are associated with multiple ocular conditions spanning both anterior and posterior segments of the eye including retinopathies. Both Cask heterozygous knockout (+/−) mice and Cask knock-in (KI) mice with reduced Cask expression have been shown to display ONH. Cask (+/−) mice displayed no defects in retinal structure or function. Here, we have systematically examined the Cask (KI) mice. Our results demonstrate that the anterior segment of the eye in Cask (KI) mice does not display any obvious phenotype. Cask (KI) mice however show a reduced visual acuity in optomotor response. The retina of Cask (KI) mice does not exhibit any major changes in their structure, vasculature, or gene expression pattern. We, however, uncovered a specific dysfunction of the cone receptor in Cask (KI) mice using electroretinogram (ERG). Mechanistically this dysfunction arises due to lowered levels of cone-specific opsin (opsin1mw) in Cask (KI) mice. To the best of our knowledge, this is the first description of retinal dysfunction in an animal model with CASK gene suppression. We infer that like ONH and cerebellar hypoplasia, retinopathy also may represent CASK LOF.