C8ORF37 Is Required for Photoreceptor Outer Segment Disc Morphogenesis by Maintaining Outer Segment Membrane Protein...

Area of Science:

• Genetics and Molecular Biology
• Ophthalmology
• Cell Biology

Background:

• C8ORF37 mutations cause incurable retinal degeneration, including retinitis pigmentosa and cone-rod dystrophy.
• The function of C8ORF37 protein has remained largely unknown, hindering understanding of disease mechanisms.

Purpose of the Study:

• To investigate the function of C8ORF37 in photoreceptor development and maintenance.
• To establish a mouse model for studying C8ORF37-associated retinal degeneration and developing therapies.

Main Methods:

• Generated a C8orf37 knockout (KO) mouse line using CRISPR/Cas9 gene editing.
• Performed comprehensive phenotypic and ultrastructural characterization of the KO mice.
• Analyzed the molecular mechanisms underlying photoreceptor degeneration.

Main Results:

• C8orf37 KO mice exhibited progressive rod and cone photoreceptor degeneration without non-ocular phenotypes.
• Massive disorganization of outer segment membrane discs was observed during development.
• Reduced levels of multiple outer segment-specific membrane proteins were detected, despite normal targeting.

Conclusions:

• C8ORF37 is essential for photoreceptor outer segment disc formation and alignment.
• C8ORF37 likely functions in the secretory pathway of the photoreceptor cell body for OS membrane protein homeostasis.
• The C8orf37 KO mouse is a valuable model for studying C8ORF37-related retinal diseases and therapeutic development.