Age-dependent disease expression determines remodeling of the retinal mosaic in carriers of RPGR exon ORF15 mutations.
OBJECTIVE
To characterize the retinal histopathology in carriers of X-linked progressive retinal atrophy (XLPRA1 and XLPRA2), two canine models of X-linked retinitis pigmentosa caused, respectively, by a stop and a frameshift mutation in RPGRORF15.


METHODS
Retinas of XLPRA2 and XLPRA1 carriers of different ages were processed for morphologic evaluation, TUNEL assay, and immunohistochemistry. Cell-specific markers were used to examine retinal remodeling events.


RESULTS
A mosaic pattern composed of patches of diseased and normal retina was first detected in XLPRA2 carriers at 4.9 weeks of age. A peak of photoreceptor cell death led to focal rod loss; however, in these patches an increased density of cones was found to persist over time. Patches of disease gradually disappeared so that by 39 weeks of age the overall retinal morphology, albeit thinner, had improved lamination. In older XLPRA2 carriers (>or=8.8 years), extended regions of severe degeneration occurred in the peripheral/mid-peripheral retina. In XLPRA1 carriers, opsin mislocalization and rare events of rod death were detected by TUNEL assay at 20 weeks of age; however, only patchy degeneration was seen by 1.4 years and was still apparent at 7.8 years.


CONCLUSIONS
The time of onset and the progression of the disease differed between the two models. In the early-onset form (XLPRA2) the morphologic appearance of the retinal mosaic changed as a function of age, suggesting that structural plasticity persists in the early postnatal canine retina as mutant photoreceptors die. In the late-onset form (XLPRA1), patches of disease persisted until later ages.
Beltran
William A
WA
School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.wbeltran@vet.upenn.edu
Acland
Gregory M
GM
Aguirre
Gustavo D
GD
D000375:Aging / Q000502:physiology*; D000818:Animals; D004283:Dog Diseases / Q000235:genetics / Q000473:pathology*; D004285:Dogs; D005091:Exons / Q000235:genetics; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000473:pathology / Q000662:veterinary*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006579:Heterozygote; D020287:In Situ Nick-End Labeling; D008297:Male; D009154:Mutation; D016366:Open Reading Frames / Q000235:genetics; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000473:pathology / Q000662:veterinary*
D020662:Guanine Nucleotide Exchange Factors