Feb 18, 2017

Pathogenic mutations in retinitis pigmentosa 2 predominantly result in loss of RP2 protein stability in humans and zebrafish

The Journal of Biological Chemistry
Fei LiuMugen Liu


Mutations in retinitis pigmentosa 2 (RP2) account for 10-20% of X-linked retinitis pigmentosa (RP) cases. The encoded RP2 protein is implicated in ciliary trafficking of myristoylated and prenylated proteins in photoreceptor cells. To date >70 mutations in RP2 have been identified. How these mutations disrupt the function of RP2 is not fully understood. Here we report a novel in-frame 12-bp deletion (c.357_368del, p.Pro120_Gly123del) in zebrafish rp2 The mutant zebrafish shows reduced rod phototransduction proteins and progressive retinal degeneration. Interestingly, the protein level of mutant Rp2 is almost undetectable, whereas its mRNA level is near normal, indicating a possible post-translational effect of the mutation. Consistent with this hypothesis, the equivalent 12-bp deletion in human RP2 markedly impairs RP2 protein stability and reduces its protein level. Furthermore, we found that a majority of the RP2 pathogenic mutations (including missense, single-residue deletion, and C-terminal truncation mutations) severely destabilize the RP2 protein. The destabilized RP2 mutant proteins are degraded via the proteasome pathway, resulting in dramatically decreased protein levels. The remaining non-destabilizing mutations T87I...Continue Reading

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Mentioned in this Paper

In Vivo
Proteasome Pathway
Carboxy-Terminal Amino Acid
Pathogenic Organism
Gene Deletion Abnormality
Gene Deletion
Mutant Proteins

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