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Wei Chieh Huang, Alejandro J. Roman, Artur V. Cideciyan, Dina Y. Gewaily, Maria P. Limberis, Peter Bell, James W. Wilson, Alan F. Wright, Anand Swaroop, Samuel G. Jacobson; X-linked RP Caused by RPGR Mutations: Natural History of the Human Disease and an Rpgr-mutant Rodent Model. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2591.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the retinal disease due to mutations in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene in human patients and a mouse model.
XLRP patients with RPGR mutations (n=20; ages at first visit 8-39 yrs) were followed longitudinally with clinical examinations and rod (R) and cone (C) perimetry. Rpgr-ko mice (ages 4-13 mos) were studied with SD-OCT and electroretinography (ERG). Matched controls were compared with the mutants. A subset of mice had retinal histopathology.
Different patterns of rod and cone dysfunction were present in the youngest patients studied (8-12 yrs). There could be detectable central R and C sensitivity, midperipheral losses, with or without peripheral R and C islands; C-only central function, midperipheral losses, and peripheral R and C function; or C-only function across the field. Over years to decades, these patterns could progress to C-only central islands without peripheral function. Less commonly, patients had central R and C scotomas but preserved, albeit abnormal, peripheral R and C function. Rpgr-ko mice had R and C ERGs that were reduced at all ages studied. At central and inferior retinal regions, mean ONL thickness was reduced by as much as 15% at 5 mos and thinned to ~50% of controls by 13 mos. Superior retina had relatively slower degeneration. There were disorganized photoreceptor inner and outer segments (IS/OS) at all stages studied.
RPGR mutations lead to major and progressive loss of rod and cone vision in human XLRP but show different patterns of residual photoreceptor disease expression. Rpgr-ko mice showed onset of degeneration at young ages and progressive rod and cone disease, as in the patients. From these results, ages for pre-clinical treatment in this model can be determined and realistic approaches to human therapy devised.
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