Ablation of the X-linked retinitis pigmentosa 2 (Rp2) gene in mice results in opsin mislocalization and photoreceptor degeneration.

Abstract

PURPOSE:

Mutations in the RP2 gene are associated with 10% to 15% of X-linked retinitis pigmentosa (XLRP), a debilitating disorder characterized by the degeneration of retinal rod and cone photoreceptors. The molecular mechanism of pathogenesis of photoreceptor degeneration in XLRP-RP2 has not been elucidated, and no treatment is currently available. This study was undertaken to investigate the pathogenesis of RP2-associated retinal degeneration.

METHODS:

We introduced loxP sites that flank exon 2, a mutational hotspot in XLRP-RP2, in the mouse Rp2 gene. We then produced Rp2-null allele using transgenic mice that expressed Cre-recombinase under control of the ubiquitous CAG promoter. Electroretinography (ERG), histology, light microscopy, transmission electron microscopy, and immunofluorescence microscopy were performed to ascertain the effect of ablation of Rp2 on photoreceptor development, function, and protein trafficking.

RESULTS:

Although no gross abnormalities were detected in the Rp2(null) mice, photopic (cone) and scotopic (rod) function as measured by ERG showed a gradual decline starting as early as 1 month of age. We also detected slow progressive degeneration of the photoreceptor membrane discs in the mutant retina. These defects were associated with mislocalization of cone opsins to the nuclear and synaptic layers and reduced rhodopsin content in the outer segment of mutant retina prior to the onset of photoreceptor degeneration.

CONCLUSIONS:

Our studies suggest that RP2 contributes to the maintenance of photoreceptor function and that cone opsin mislocalization represents an early step in XLRP caused by RP2 mutations. The Rp2(null) mice should serve as a useful preclinical model for testing gene- and cell-based therapies.

• Authors: Linjing Li, Naheed Khan, Toby Hurd, Amiya Kumar Ghosh, Christiana Cheng, Robert Molday, John R Heckenlively, Anand Swaroop, Hemant Khanna
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 54 Issue 7 Pg. 4503-11 (Jul 02 2013) ISSN: 1552-5783 [Electronic] United States
• PMID: 23745007 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Eye Proteins
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• Opsins
• RP2 protein, human
• GTP-Binding Proteins

Topics

• Animals
• Disease Models, Animal
• Electroretinography
• Eye Proteins (genetics)
• GTP-Binding Proteins
• Genes, X-Linked (genetics)
• Genetic Diseases, X-Linked (genetics, pathology, physiopathology)
• Intracellular Signaling Peptides and Proteins (deficiency, genetics)
• Membrane Proteins (deficiency, genetics)
• Mice
• Opsins (metabolism)
• Photoreceptor Cells (pathology)
• Retinitis Pigmentosa (genetics, pathology, physiopathology)