THE PHYSIOPATHOLOGY OF RETINITIS PIGMENTOSA TYPE 10 BY MUTATIONS IN INOSINE MONOPHOSPHATE DEHYDROGENASE 1 INVOLVES THE FORMATION OF LONG-LIVED CYTOOPHIDIA

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 a hallmark of the disease is the formation of long-lived, irreversible IMPDH1 cytoophidia. We here aimed to demonstrate that the formation of these protein assemblies mediates the physiopathology of the disease. A point-of-separation mutation, R356A, was introduced in the Impdh1 mutated allele of D226N/IMPDH1 mice by CRISPR/Cas9. This mutation is known to impair IMPDH1 filament formation in vitro without affecting its catalytic activity. A time-course analysis of retinal morphology and visual function was performed in D226N/R356A/IMPDH1 versus D226N/IMPDH1 mice. While D226N heterozygous mice showed a progressive retinal degeneration that reduced the number of photoreceptor cells by >35% at postnatal day 60 and by >50% by 7 months of age, the double mutant D226N/R356A/IMPDH1 mice showed a mild retinal degeneration (20% loss of photoreceptors) at postnatal day 30, that was stalled at this point. The retinal degeneration did not progress with age, and mice at 2 and 7 months of age retained 9-10 rows of photoreceptor nuclei in their retinas. Visual function, as assessed by electroretinogram recordings, was also preserved. We conclude that the formation of long-lived cytoophidia is at the core of adRP10 physiopathology, and that the process of IMPDH1 filament assembly should be considered a therapeutic target for this disease.