RPGR-associated retinal degeneration in human X-linked RP and a murine model.
OBJECTIVE
We investigated the retinal disease due to mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene in human patients and in an Rpgr conditional knockout (cko) mouse model.


METHODS
XLRP patients with RPGR-ORF15 mutations (n = 35, ages at first visit 5-72 years) had clinical examinations, and rod and cone perimetry. Rpgr-cko mice, in which the proximal promoter and first exon were deleted ubiquitously, were back-crossed onto a BALB/c background, and studied with optical coherence tomography and electroretinography (ERG). Retinal histopathology was performed on a subset.


RESULTS
Different patterns of rod and cone dysfunction were present in patients. Frequently, there were midperipheral losses with residual rod and cone function in central and peripheral retina. Longitudinal data indicated that central rod loss preceded peripheral rod losses. Central cone-only vision with no peripheral function was a late stage. Less commonly, patients had central rod and cone dysfunction, but preserved, albeit abnormal, midperipheral rod and cone vision. Rpgr-cko mice had progressive retinal degeneration detectable in the first months of life. ERGs indicated relatively equal rod and cone disease. At late stages, there was greater inferior versus superior retinal degeneration.


CONCLUSIONS
RPGR mutations lead to progressive loss of rod and cone vision, but show different patterns of residual photoreceptor disease expression. Knowledge of the patterns should guide treatment strategies. Rpgr-cko mice had onset of degeneration at relatively young ages and progressive photoreceptor disease. The natural history in this model will permit preclinical proof-of-concept studies to be designed and such studies should advance progress toward human therapy.
Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Wei Chieh
WC
Huang
Alan F
AF
Wright
Alejandro J
AJ
Roman
Artur V
AV
Cideciyan
Forbes D
FD
Manson
Dina Y
DY
Gewaily
Sharon B
SB
Schwartz
Sam
S
Sadigh
Maria P
MP
Limberis
Peter
P
Bell
James M
JM
Wilson
Anand
A
Swaroop
Samuel G
SG
Jacobson
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D017949:Retinal Cone Photoreceptor Cells / Q000502:physiology; D012162:Retinal Degeneration / Q000235:genetics* / Q000503:physiopathology; D017948:Retinal Rod Photoreceptor Cells / Q000502:physiology; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000503:physiopathology; D014792:Visual Acuity; D055815:Young Adult
D005136:Eye Proteins; C099929:RPGR protein, human