Knockout of RP2 decreases GRK1 and rod transducin subunits and leads to photoreceptor degeneration in zebrafish

Liu, F., Chen, J., Yu, S., Raghupathy, R.K., Liu, X., Qin, Y., Li, C., Huang, M., Liao, S., Wang, J., Zou, J., Shu, X., Tang, Z., Liu, M.
Human molecular genetics   24(16): 4648-59 (Journal)
Registered Authors
Liu, Mugen
MeSH Terms
  • Animals
  • Eye Proteins
  • G-Protein-Coupled Receptor Kinase 1/genetics
  • G-Protein-Coupled Receptor Kinase 1/metabolism*
  • Gene Knockdown Techniques
  • Genetic Diseases, X-Linked/genetics
  • Genetic Diseases, X-Linked/metabolism*
  • Genetic Diseases, X-Linked/pathology
  • Mice
  • Photoreceptor Cells, Vertebrate/metabolism*
  • Photoreceptor Cells, Vertebrate/pathology
  • Retinitis Pigmentosa/genetics
  • Retinitis Pigmentosa/metabolism*
  • Retinitis Pigmentosa/pathology
  • Transducin/genetics
  • Transducin/metabolism*
  • Zebrafish
  • Zebrafish Proteins/deficiency*
26034134 Full text @ Hum. Mol. Genet.
Retinitis pigmentosa (RP) affects about 1.8 million individuals worldwide. X-linked retinitis pigmentosa (XLRP) is one of the most severe forms of RP. Nearly 85% of XLRP cases are caused by mutations in the X-linked retinitis pigmentosa 2 (RP2) and RPGR. RP2 has been considered to be a GTPase activator protein for ARL3 and to play a role in the traffic of ciliary proteins. The mechanism of how RP2 mutations cause retinitis pigmentosa is still unclear. In this study, we generated an RP2 knockout zebrafish line using TALEN technology. Progressive retinal degeneration could be observed in the mutant zebrafish. The degeneration of rods' outer segments is predominant, followed by the degeneration of cones' outer segments. These phenotypes are similar to the characteristics of RP2 patients, and also partly consistent with the phenotypes of RP2 knockout mice and morpholino mediated RP2 knockdown zebrafish. For the first time, we found RP2 deletion leads to decreased protein levels and abnormal retinal localizations of GRK1 and rod transducin subunits (GNAT1 and GNB1) in zebrafish. Furthermore, the distribution of the total farnesylated proteins in zebrafish retina is also affected by RP2 ablation. These molecular alterations observed in the RP2 knockout zebrafish might probably be responsible for the gradual loss of the photoreceptors' outer segments. Our work identified the progression of retinal degeneration in RP2 knockout zebrafish, provided a foundation for revealing the pathogenesis of retinitis pigmentosa caused by RP2 mutations, and would help to develop potential therapeutics against retinitis pigmentosa in further studies.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes