A frameshift mutation in RPGR exon ORF15 causes photoreceptor degeneration and inner retina remodeling in a model of X-linked retinitis pigmentosa.
OBJECTIVE
To characterize the course of retinal disease in X-linked progressive retinal atrophy 2 (XLPRA2), a canine model of early onset X-linked retinitis pigmentosa (XLRP) caused by a two-nucleotide microdeletion in RPGR ORF15.


METHODS
The retinas of 25 XLPRA2-affected dogs (age range, 2-40.6 weeks) and age-matched control subjects were collected, fixed, and embedded in epoxy resin for morphologic evaluation or in optimal cutting temperature (OCT) medium for TUNEL assay and immunohistochemistry. Cell-specific antibodies were used to examine changes in rods and cones and to evaluate the effects of the primary photoreceptor degeneration on inner retinal cells.


RESULTS
Abnormal development of photoreceptors was recognizable as early as 3.9 weeks of age. Outer segment (OS) misalignment was followed by their disorganization and fragmentation. Reduction in length and broadening of rod and cone inner segments (IS) was next observed, followed by the focal loss of rod and cone IS at later time points. The proportion of dying photoreceptors peaked at approximately 6 to 7 weeks of age and was significantly reduced after 12 weeks. In addition to rod and cone opsin mislocalization, there was early rod neurite sprouting, retraction of rod bipolar cell dendrites, and increased Müller cell reactivity. Later in the course of the disease, changes were also noted in horizontal cells and amacrine cells.


CONCLUSIONS
XLPRA2 is an early-onset model of XLRP that is morphologically characterized by abnormal photoreceptor maturation followed by progressive rod-cone degeneration and early inner retina remodeling. The results suggest that therapeutic strategies for this retinal degeneration should target not solely photoreceptor cells but also inner retinal neurons.
Beltran
William A
WA
James A. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York, USA.
Hammond
Pamela
P
Acland
Gregory M
GM
Aguirre
Gustavo D
GD
D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D018450:Disease Progression; D004283:Dog Diseases / Q000235:genetics / Q000473:pathology*; D004285:Dogs; D005091:Exons / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D016368:Frameshift Mutation; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000473:pathology / Q000662:veterinary*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D020287:In Situ Nick-End Labeling; D008297:Male; D016366:Open Reading Frames / Q000235:genetics; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000473:pathology / Q000662:veterinary*
D005136:Eye Proteins; D020662:Guanine Nucleotide Exchange Factors; C099929:RPGR protein, human