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Mutations in the retinitis pigmentosa 1 ( RP1 ) gene are a common cause of autosomal dominant retinitis pigmentosa (adRP), and have also been found to cause autosomal recessive RP (arRP) in a few families. The 33 dominant mutations and 6 recessive  RP1  mutations identified to date are all nonsense or frameshift mutations, and almost exclusively (38 out of 39) are located in the 4 th  and final exon of  RP1 . To better understand the underlying disease mechanisms of and help develop therapeutic strategies for RP1 disease, we performed a series of human genetic and animal studies using gene targeted and transgenic mice. Here we report that a frameshift mutation in the 3 rd  exon of  RP1  (c.686delC; p.P229QfsX35) found in a patient with recessive  RP1  disease causes RP in the homozygous state, whereas the heterozygous carriers are unaffected, confirming that haploinsufficiency is not the causative mechanism for  RP1  disease. We then generated  Rp1  knock-in mice with a nonsense Q662X mutation in exon 4, as well as  Rp1  transgenic mice carrying a wild-type BAC  Rp1  transgene. The  Rp1 -Q662X allele produces a truncated Rp1 protein, and homozygous  Rp1 -Q662X mice experience a progressive photoreceptor degeneration characterized disorganization of photoreceptor outer segments. This phenotype could be prevented by expression of a normal amount of Rp1 protein from the BAC transgene without removal of the mutant Rp1-Q662X protein. Over-expression of Rp1 protein in additional BAC  Rp1  transgenic lines resulted in retinal degeneration. These findings suggest that the truncated Rp1-Q662X protein does not exert a toxic gain-of-function effect. These results also imply that in principle gene augmentation therapy could be beneficial for both recessive and dominant  RP1  patients, but the levels of RP1 protein delivered for therapy will have to be carefully controlled.

Expression of Wild-Type Rp1 Protein in Rp1 Knock-in Mice Rescues the Retinal Degeneration Phenotype