Although three different loci (RP3, RP2 and RP15) have been proposed on the short arm of the X-chromosome by linkage analysis, RP3 represents the disease locus in the majority of XLRP families.
Canine X-linked progressive retinal atrophy (XLPRA) is caused by mutations in RPGR exon ORF15, which is also a mutation hotspot in human X-linked retinitis pigmentosa 3 (RP3).
Deep intronic mutation in OFD1, identified by targeted genomic next-generation sequencing, causes a severe form of X-linked retinitis pigmentosa (RP23).
Eleven carriers from two families with XLRP and mutations in RPGR underwent clinical examination including fundus photography, AF, full-field electroretinography, Goldmann kinetic perimetry and two-colour threshold perimetry (2CT perimetry).
Gene replacement therapy for RPGR-XLRP was hampered by the relatively slow disease progression in mouse models and by difficulties in cloning the full-length RPGR-ORF15 cDNA that includes a purine-rich 3'-coding region; however, its effectiveness has recently been demonstrated in four dogs with RPGR mutations.
Here we report the generation and characterization of a new mouse model for X-linked retinitis pigmentosa (XLRP) carrying a point mutation in the mutational hotspot exon ORF15 of the RPGR gene as well as a recognition site for the homing endonuclease I-SceI.
Here, we describe an optimized gene replacement therapy for human XLRP disease using an AAV8 vector that reliably and consistently produces the full-length correct RPGR protein.
Here, we highlight the translational progress of gene therapy and genome editing of several retinal disorders, including RPE65-, CEP290-, and GUY2D-associated Leber congenital amaurosis, as well as choroideremia, achromatopsia, Mer tyrosine kinase- (MERTK-) and RPGRX-linked retinitis pigmentosa, Usher syndrome, neovascular age-related macular degeneration, X-linked retinoschisis, Stargardt disease, and Leber hereditary optic neuropathy.
Heterozygous carriers of X-linked retinitis pigmentosa with these specific RPGR genotypes also show a variability of the phenotype; carriers with the microdeletion may be severely visually handicapped.
Identification of novel RPGR (retinitis pigmentosa GTPase regulator) mutations in a subset of X-linked retinitis pigmentosa families segregating with the RP3 locus.
In addition, further investigation of XLRP carriers may yield insight into how cone structures change over time and ultimately enable understanding of the role of RPGR and RP2 in cone cell survival.