Non-Cell Autonomous Roles for CASK in Optic Nerve Hypoplasia

Area of Science:

• Genetics
• Neuroscience
• Ophthalmology

Background:

• X-linked CASK gene mutations are linked to optic nerve hypoplasia (ONH) and retinal disorders in females.
• CASK+/- mice show ONH and retinal ganglion cell (RGC) loss, but the specific cellular targets and CASK's role in RGCs remain unclear.

Purpose of the Study:

• To investigate the role of CASK in retinal cell function and optic nerve development.
• To determine if CASK deficiency selectively impacts RGCs or other retinal cells.
• To assess the necessity of CASK expression in RGCs for optic nerve development and maintenance.

Main Methods:

• Assessed visual behavior and performed electroretinography (ERG) in CASK+/- mice.
• Utilized a floxed CASK mouse model to study global CASK reduction (hypomorph) and cell-specific deletion in RGCs.
• Reported a novel hemizygous CASK missense mutation in a boy with ONH.

Main Results:

• CASK+/- mice exhibited reduced visual contrast sensitivity, with normal ERG.
• CASK hypomorph mice showed ONH, but RGC-specific CASK deletion did not worsen the condition.
• The identified mutation in the boy destabilized CASK and impaired its interaction with neurexin.

Conclusions:

• Mosaic or reduced CASK expression disproportionately affects RGCs.
• CASK expression within RGCs is not essential for their survival.
• CASK plays a non-cell-autonomous role in optic nerve development.