Abstract
Purpose :
Optic nerve hypoplasia (ONH) is the most common cause of childhood blindness in developed nations. Despite increasing incidence of ONH, the fundamental pathobiology of ONH remains unclear. Mutations in the X-linked gene CASK have been associated with ONH. Haploinsufficiency of CASK gene is associated with ONH in human and mice. ONH in CASK(+/-) mice is characterized by loss of retinal ganglion cells (RGCs) as well as atrophy of RGC axons. Are other cell-types in retina affected with CASK mutation? What is the cellular origin of ONH with CASK mutations?
Methods :
To answer these questions, we perform retinal imaging, electroretinogram and visual behavior experiments on CASK(+/-) mice. Furthermore, we also analyze a knockin mice with floxed CASK gene and a mouse line where CASK is specifically deleted from majority of RGCs. Finally, we present phenotype from two different subjects with two different CASK mutation to identify probable molecular mechanism of CASK-linked ONH.
Results :
Overall lamination of retina is unperturbed in CASK(+/-) mice. Electroretinogram from the CASK(+/-) mice is within normal range and vision is only marginally affected. Presence of neomycin cassette within CASK gene of the CASK(floxed) mice reduces the expression of CASK by ~60% in optic nerve (hypomorph). Although, we uncover loss of RGCs as well as thinning of optic nerve in this hypomorph mouse line, we did not observe RGC axonal atrophy as seen in CASK(+/-) mice. The histopathology therefore are distinct in these two different ONH models developed by perturbation in the same gene. Specific deletion of CASK from RGC in the CASK hypomorph background also fails to phenocopy the axonal atrophy seen in CASK(+/-) mice. Finally, we identify two different mis-sense mutations in CASK gene associated with two different ophthalmic conditions. Leucine 209 proline (L209P) is associated with bilateral retinal dystrophy and optic nerve atrophy while proline 673 leucine (P673L) is associated with ONH. P673L but not L209P disrupts CASK-neurexin interaction.
Conclusions :
Overall our data suggests that although CASK loss-of function predominantly affects RGCs, the pathology may not be cell-autonomous and is unlikely to arise from RGC itself. Furthermore, CASK-neurexin interaction is critical for optic nerve development.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.