RETGC ACTIVITY IS PROTECTIVE IN IMPDH1-ASSOCIATED AUTOSOMAL DOMINANT RETINITIS PIGMENTOSA

Autosomal dominant retinitis pigmentosa type 10 (adRP10) is caused by mutations in Inosine Monophosphate Dehydrogenase 1 (IMPDH1) and accounts for 2,5% of all RP patients. There is no current treatment for this disease. We have recently established a mouse model of adRP10, the D226N/IMPDH1 mice, and showed that the mutant protein results in a nucleotide imbalance in retinal extracts. IMP and adenine nucleotide levels are decreased, while guanine nucleotides are maintained. This is likely due to the abrogation of the GTP/GDP sensor for allosteric inhibition in the mutant protein, that leads to constitutive catalytic activity. IMPDH1 catalyzes the first committed step to guanine nucleotide synthesis. Its constitutive activity would increase the flux towards guanine nucleotide synthesis. To study whether the basis of the physiopathology in adRP10 is an abnormal increase in cGMP levels, a well-established cause of photoreceptor cell death, we abrogated retinal guanylate cyclase (RetGC) activity in D226N/IMPDH1 mice. We here report that breeding D226N/IMPDH1 mice to RetGC1/RetGC2 double knockout mice severely exacerbated the retinal degeneration phenotype, causing the loss of >90% of photoreceptors by postnatal day 60 [versus the loss of 30% of photoreceptors in D226N mice at p60]. This was an striking result, given that the RetGC1/RetGC2 dKO mice show a well-preserved retinal morphology. The histological landmark of this disease, IMPDH1 cytoophidia, is first observed at photoreceptor axonic terminals in these mice during postnatal development. We conclude that cGMP synthesis by RetGCs at rod and cone axonic terminals is protective in the context of this disease.