*5.3. CEP290*

This cat model, *rdAc* (retinal degeneration, Abyssinian cat) has been studied in detail for many years. Compared to most *CEP290* (centrosomal protein 290) mutations in other species, the cat model has a mild phenotype. The onset and rate of photoreceptor degeneration in the cat with the sparing of the area centralis makes it a model for RP [96,97]. In humans, *CEP290* mutations can result in a spectrum of phenotypes including lethality, severe syndromic disease (e.g., Joubert syndrome) and most commonly LCA; see [98] for a review. Milder phenotypes such as RP are less common. In the cat, an intronic mutation (c.6966+9T>G) leads to the introduction of a stronger splice acceptor site (the wildtype splice acceptor is a GC rather than the much more commonly used GT). The mutation strengthens an adjacent GT, which, when used, adds 4 bps to the exon 50 sequence, the resulting frameshift introduces a premature stop codon [99]. The truncated protein escapes nonsense mediated decay and is expressed. In addition, the wildtype acceptor site is still used for a percentage of the transcripts (unpublished data). The combination of a truncated protein with some remaining function combined with a low-level production of full-length transcripts explains the mild phenotype. *CEP290* is too large to be packaged in an adeno-associated virus vector and one therapeutic approach being investigated is the use of a truncated transcript so that a miniprotein may have partial function and convert a severe phenotype into a milder phenotype similar to that of the cat.
