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PMID:28209709

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Citation

Liu, F, Qin, Y, Yu, S, Soares, DC, Yang, L, Weng, J, Li, C, Gao, M, Lu, Z, Hu, X, Liu, X, Jiang, T, Liu, JY, Shu, X, Tang, Z and Liu, M (2017) Pathogenic mutations in retinitis pigmentosa 2 predominantly result in loss of RP2 protein stability in humans and zebrafish. J. Biol. Chem. 292:6225-6239

Abstract

Mutations in retinitis pigmentosa 2 () 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 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 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 markedly impairs RP2 protein stability and reduces its protein level. Furthermore, we found that a majority of the 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, R118H/R118G/R118L/R118C, E138G, and R211H/R211L are suggested to impair the interaction between RP2 and its protein partners (such as ARL3) or with as yet unknown partners. By utilizing a combination of , , and approaches, our work comprehensively indicates that loss of RP2 protein structural stability is the predominating pathogenic consequence for most mutations. Our study also reveals a role of the C-terminal domain of RP2 in maintaining the overall protein stability.

Links

PubMed PMC5391753 Online version:10.1074/jbc.M116.760314

Keywords

Animals; Base Sequence; Eye Proteins/genetics; Eye Proteins/metabolism; Humans; Intracellular Signaling Peptides and Proteins/genetics; Intracellular Signaling Peptides and Proteins/metabolism; Membrane Proteins/genetics; Membrane Proteins/metabolism; Protein Domains; Protein Stability; Retinal Degeneration/genetics; Retinal Degeneration/metabolism; Sequence Deletion; Zebrafish/genetics; Zebrafish/metabolism; Zebrafish Proteins/genetics; Zebrafish Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:XRP2

involved_in

GO:0045494: photoreceptor cell maintenance

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-170615-12

P

Seeded From UniProt

complete

DANRE:F1QC45

involved_in

GO:0045494: photoreceptor cell maintenance

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-170615-12

P

Seeded From UniProt

complete

Notes

See also

References

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