title: Rd9 is a naturally occurring mouse model of a common form of retinitis pigmentosa caused by mutations in RPGR-ORF15.
abstract: Animal models of human disease are an invaluable component of studies aimed at understanding disease pathogenesis and therapeutic possibilities. Mutations in the gene encoding retinitis pigmentosa GTPase regulator (RPGR) are the most common cause of X-linked retinitis pigmentosa (XLRP) and are estimated to cause 20% of all retinal dystrophy cases. A majority of RPGR mutations are present in ORF15, the purine-rich terminal exon of the predominant splice-variant expressed in retina. Here we describe the genetic and phenotypic characterization of the retinal degeneration 9 (Rd9) strain of mice, a naturally occurring animal model of XLRP. Rd9 mice were found to carry a 32-base-pair duplication within ORF15 that causes a shift in the reading frame that introduces a premature-stop codon. Rpgr ORF15 transcripts, but not protein, were detected in retinas from Rd9/Y male mice that exhibited retinal pathology, including pigment loss and slowly progressing decrease in outer nuclear layer thickness. The levels of rhodopsin and transducin in rod outer segments were also decreased, and M-cone opsin appeared mislocalized within cone photoreceptors. In addition, electroretinogram (ERG) a- and b-wave amplitudes of both Rd9/Y male and Rd9/Rd9 female mice showed moderate gradual reduction that continued to 24 months of age. The presence of multiple retinal features that correlate with findings in individuals with XLRP identifies Rd9 as a valuable model for use in gaining insight into ORF15-associated disease progression and pathogenesis, as well as accelerating the development and testing of therapeutic strategies for this common form of retinal dystrophy.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Debra A
authors.initials: DA
authors.lastname: Thompson
authors.forename: Naheed W
authors.initials: NW
authors.lastname: Khan
authors.forename: Mohammad I
authors.initials: MI
authors.lastname: Othman
authors.forename: Bo
authors.initials: B
authors.lastname: Chang
authors.forename: Lin
authors.initials: L
authors.lastname: Jia
authors.forename: Garrett
authors.initials: G
authors.lastname: Grahek
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Wu
authors.forename: Suja
authors.initials: S
authors.lastname: Hiriyanna
authors.forename: Jacob
authors.initials: J
authors.lastname: Nellissery
authors.forename: Tiansen
authors.initials: T
authors.lastname: Li
authors.forename: Hemant
authors.initials: H
authors.lastname: Khanna
authors.forename: Peter
authors.initials: P
authors.lastname: Colosi
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
authors.forename: John R
authors.initials: JR
authors.lastname: Heckenlively
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004596:Electroretinography; D005091:Exons / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D012160:Retina / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012243:Rhodopsin / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid
chemical_list: D002352:Carrier Proteins; D005136:Eye Proteins; C513598:RPGR protein, mouse; D012243:Rhodopsin