Retinal Degeneration in Mice Lacking the Cyclic Nucleotide-Gated Channel Subunit CNGA1

Cyclic nucleotide-gated (CNG) channels are important mediators in the transduction pathways of rod and cone photoreceptors. Native CNG channels are heterotetramers composed of homologous A and B subunits. Biallelic mutations in CNGA1 or CNGB1 genes result in autosomal recessive retinitis pigmentosa (RP). To investigate the pathogenic mechanism of CNG channel-associated retinal degeneration, we developed a mouse model of CNGA1 knock-out using CRISPR/Cas9 technology. RNA-sequencing analysis of the retinae suggested down-regulated synaptic transmission and phototransduction as early as 9 days postnatal, possibly inducing later photoreceptor degeneration. In addition, the down-regulated PI3K-AKT-mTOR pathway indicated upregulation of autophagic process, and chaperone-mediated autophagy was further shown to coincide with the time course of photoreceptor death. Taken together, our studies add to a growing body of research exploring the mechanisms of photoreceptor death during RP progression and provide a novel CNGA1 knockout mouse model for potential therapies development.