TULP1 missense mutations cause variable retinal phenotypes and activation of the endoplasmic reticulum unfolded...

Mutations in TULP1 are associated with early-onset forms of inherited retinal degenerations (IRDs). Evidence from Tulp1-/- mice indicates that TULP1 plays a role in photoreceptor protein trafficking. Here we generated two novel knock-in mouse models, each expressing the ortholog to a human IRD-causing homozygous missense TULP1 mutation to: 1) better recapitulate IRD patients' gene dosage and spatiotemporal degeneration, 2) determine the pathological disease mechanism, and 3) evaluate mutations affecting different domains of the protein. The Tulp1F492L model carries a mutation affecting a conserved amino acid in the C-terminal tubby domain, whereas the Tulp1D89Y model carries the only homozygous mutation located outside the tubby domain. In both mutant retinas, TULP1F492L and TULP1D89Y protein levels and distribution were comparable to WT. Surprisingly, variable retinal phenotypes were observed in the two mutant lines. The Tulp1F492L model displayed rapid photoreceptor degeneration, rod and cone opsin mistrafficking, and abnormal shaped ribbon synapses, similar to Tulp1-/- mice. In contrast, these abnormalities were not seen in the Tulp1D89Y model; indeed, retinal morphology and function was preserved up to 12 months, although we noted less RPE pigmentation and dilated structures in the outer plexiform layer at this timepoint. Moreover, building on our prior in vitro results, we observed activation of the IRE1 branch of the endoplasmic reticulum (ER)-unfolded protein response (UPR) complex in Tulp1-/- and Tulp1F492L retinas, identifying ER stress as a key disease mechanism leading to photoreceptor death and as a potential therapeutic target in TULP1-associated forms of IRD.