BASIS OF PHYSIOPATHOLOGY IN A NOVEL MURINE MODEL OF AUTOSOMAL DOMINANT RETINITIS PIGMENTOSA TYPE 10 BY MUTATIONS IN INOSINE MONOPHOSPHATE DEHYDROGENASE 1

The mechanisms underlying the physiopathology of autosomal dominant retinitis pigmentosa type 10 (adRP10) caused by mutations in Inosine Monophosphate Dehydrogenase 1 (IMPDH1) remain unknown. There is no current treatment for this disease, that accounts for 2,5% of all RP patients. We established a mouse model of the disease by introducing the D226N mutation in the endogenous Impdh1 gene by CRISPR/Cas9. A time-course analysis of retinal morphology and visual function was performed in D226N/IMPDH1 mice. Heterozygous mice showed a progressive retinal degeneration that reduced the number of photoreceptor cells by 35% at postnatal day 40, and by >50% by seven months of age. Homozygous mice showed a loss of 35% of photoreceptor cells at p25 and of > 60% at p40. Electroretinogram (ERG) recordings showed a correlating loss of visual function. D226N/IMPDH1 mice presented a substantial increase in the GTP/IMP ratio in retinal homogenates, as assessed by high pressure liquid chromatography and mass spectrometry. This nucleotide imbalance results from the constitutive activity of the mutant protein. While control wild type mice only show IMPDH1 cytoophidia after long periods of bright light exposure that are reverted by dark adaptation, a hallmark of D226N/IMPDH1 mice was the abundance of long-lived cytoophidia independently of the dark/light-adaptation conditions. In conclusion, the first murine model of adRP10 faithfully mimics the disease in patients and shows that the mutant protein causes the disease by: i) a nucleotide imbalance; and ii) formation of long-lived irreversible cytoophidia. Phenotypic rescue attempts are being conducted by methods transferable to patients.