Several
Rpgr mutant rodent models have been investigated to date. In addition to the pursuit of greater understanding of the disease mechanism, the models can provide opportunities for proof-of-concept studies that may advance therapeutic interventions relevant to human
RPGR-XLRP. Reported models differ in genotype and background strain, with phenotypes showing different degrees and time courses of structural and functional losses. Available data on the disease expression for several of these rodent models are summarized (
Supplementary Table S1). The naturally-occurring
rd9 mouse shows a relatively moderate disease phenotype, with ERGs decreasing to 60 to 70% of normal at 3 to 5 months, 50% at 11 to 16 months, and 35% at 24 months of age.
57 A genetically-engineered
Rpgr-null mouse
12,14,58 showed moderate degeneration, with dysfunction reaching 69 to 75% of normal levels at 6 months of age. ONL loss of approximately 50% was observed at 24 months of age. Addition of a mutant ORF15 transgene
14 to the
Rpgr-
null mouse produced a severe disease phenotype with rod ERGs decreasing to 10% of normal levels, and 50% of structural loss 40 days after birth. The faster degeneration rate in this model has been attributed to a gain-of-function mechanism.
14 A different ORF15 transgene was introduced into the
Rpgr-null mouse, resulting in preservation of ONL thickness and partial recovery of visual function when compared to WT at 14 months of age.
58 The addition of transgenes causing overexpression of two otherwise normal
Rpgr variants (mRDef, Rpgr
ex1-19 and mRORF, Rpgr-ORF15)to the
Rpgr-
null mouse produced either a severe degeneration in the first variant (ONL reduction to 22% of normal by 3–5 months), or the preservation of ONL thickness with possible rescue of the phenotype for the second (no loss observed up to age 3–5 months; the mRORF transgene also was reported not to be deleterious when applied to a WT background). The faster degeneration in the mRDef model was postulated to be related to abnormal accumulations of Rpgr
ex1-19 in the photoreceptor outer segment.
16 An exon 4 knockout was engineered and introduced to mice on either BALB/c (
Rpgr ΔEx4 BALB/c) or C57BL/6 (
Rpgr ΔEx4 BL/6) backgrounds by another group,
15 resulting in relatively milder degeneration rates. A difference in phenotype also was found to correlate with the mouse background strain; the
Rpgr ΔEx4 BALB/c showed a comparatively faster cone degeneration rate by ERG, reaching ∼40% of normal levels by 12 months of age, but no detectable structural loss, whereas the
Rpgr ΔEx4 BL/6 showed some reduction of ONL thickness, reaching a level of ∼85% of normal at 12 months of age. The exon 1 conditional knockout on a BALB/c background presented in our study showed progressive retinal degeneration and visual function loss, and the data suggest a faster degeneration rate than the moderate models described previously. By ∼6 months of age, rod and cone ERGs showed a reduction of ∼40% compared to normal levels. ONL thickness (by SD-OCT) was reduced to 35% of WT at ∼13 months. Cone and rod ERG amplitude reduction as well as structural loss appear faster than in the reported data for the
Rpgr ΔEx4 BALB/c model and without evidence of cone more than rod dysfunction (
Supplementary Table S1).