Do the retinal abnormalities in X-linked juvenile retinoschisis include impaired phototransduction?

Abstract

X-linked juvenile retinoschisis (XLRS), a hereditary retinal disorder primarily affecting males, is characterized by the formation of cystic spaces between the outer plexiform layer and outer nuclear layer of the retina. Mutations in the RS1 gene, which encodes the extracellular binding protein retinoschisin, are responsible for XLRS pathogenesis. While the role of retinoschisin in maintaining retinal integrity is well established, there is growing evidence suggesting compromised photoreceptor function in XLRS. To investigate the molecular pathways affected by RS1 deficiency, particularly in phototransduction, we performed electroretinographic (ERG) and proteomic analyses on retinae from Rs1 knockout mice, a model of human XLRS. The Rs1 knockout mice had reduced ERG a-wave amplitudes. Correspondingly, differential expression analysis revealed downregulation of proteins crucial for phototransduction, with Ingenuity Pathway Analysis (IPA) highlighting "phototransduction" as the most significantly downregulated biological theme. Compensatory mechanisms were also observed in the IPA, including upregulation of synaptic remodeling, inflammation, cell adhesion, and G-protein signaling. These findings strongly implicate an underrecognized role of photoreceptor dysfunction in XLRS pathology. We speculate that entrapment of mutant retinoschisin protein within photoreceptor inner segments as well as disrupted reciprocal regulation between L-type voltage-gated calcium channels and retinoschisin contribute to the dysfunction in photoreceptors.

• Authors: Lucia Ambrosio, James D Akula, Jarrod C Harman, Ivana A Arellano, Anne B Fulton
• Journal: Experimental eye research (Exp Eye Res) Vol. 234 Pg. 109591 (09 2023) ISSN: 1096-0007 [Electronic] England
• PMID: 37481224 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023. Published by Elsevier Ltd.

Chemical References

• Cell Adhesion Molecules
• Eye Proteins

Topics

• Humans
• Male
• Animals
• Mice
• Retinoschisis (genetics)
• Proteomics
• Cell Adhesion Molecules (genetics)
• Retina (metabolism)
• Mice, Knockout
• Eye Proteins (metabolism)