RPGR ORF15 genotype and clinical variability of retinal degeneration in an Australian population

Ruddle, Jonathan B; Ebenezer, Neil D.; Kearns, Lisa S.; Mulhall, Lindsay E; Mackey, David A.; Hardcastle, Alison J.

doi:10.1136/bjo.2008.153908

Cited by 25 publications

(18 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1A, P2). The present examples, taken together with previous observations (16,(25)(26)(27)(28)(29)(30), demonstrate that there can be a spectrum of human RPGR-XLRP phenotypes. Most of the phenotypes have more rod than cone dysfunction as measured by electroretinograms (ERGs) (30).…”

Section: Rpgr Orf15 Mutations Lead To Photoreceptor Degeneration Inmentioning

confidence: 94%

Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa

Beltran

Cideciyan

Lewin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

236

260

View full text Add to dashboard Cite

Hereditary retinal blindness is caused by mutations in genes expressed in photoreceptors or retinal pigment epithelium. Gene therapy in mouse and dog models of a primary retinal pigment epithelium disease has already been translated to human clinical trials with encouraging results. Treatment for common primary photoreceptor blindness, however, has not yet moved from proof of concept to the clinic. We evaluated gene augmentation therapy in two blinding canine photoreceptor diseases that model the common X-linked form of retinitis pigmentosa caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, which encodes a photoreceptor ciliary protein, and provide evidence that the therapy is effective. After subretinal injections of adeno-associated virus-2/5-vectored human RPGR with human IRBP or GRK1 promoters, in vivo imaging showed preserved photoreceptor nuclei and inner/ outer segments that were limited to treated areas. Both rod and cone photoreceptor function were greater in treated (three of four) than in control eyes. Histopathology indicated normal photoreceptor structure and reversal of opsin mislocalization in treated areas expressing human RPGR protein in rods and cones. Postreceptoral remodeling was also corrected: there was reversal of bipolar cell dendrite retraction evident with bipolar cell markers and preservation of outer plexiform layer thickness. Efficacy of gene therapy in these large animal models of X-linked retinitis pigmentosa provides a path for translation to human treatment.retina | retinal degeneration P hotoreceptors function cooperatively with the retinal pigment epithelium (RPE) to optimize photon catch and generate signals that are transmitted to higher vision centers and perceived as a visual image. Disruption of the visual process in the retinal photoreceptors can result in blindness. Genetic defects in the retina cause substantial numbers of sight-impairing disorders by a multitude of mechanisms (1, 2). These genetic diseases were classically considered incurable, but the past few years have witnessed a new era of retinal therapeutics in which successful gene therapy of an animal model of one blinding human disease (3) was followed by stepwise translation to the clinic. The RPE65 form of Leber congenital amaurosis, due to a biochemical blockade of the retinoid cycle in the RPE, was the first and remains the only blinding genetic disease to be successfully treated in humans (reviewed in ref. 4).The next level of challenge is to initiate treatment for the majority of blinding retinal disorders in which the genetic flaws are primarily in the photoreceptors. Successful targeting of therapeutic vectors to mutant photoreceptors would be required to restore function and preserve structure. Among photoreceptor dystrophies, the X-linked forms of retinitis pigmentosa (XLRP) are one of the most common causes of severe vision loss (5). More than 25 y ago, the genetic loci were identified (6), and discovery of the underlying gene defects followed (7,8). Mutations in the reti...

show abstract

Section: Rpgr Orf15 Mutations Lead To Photoreceptor Degeneration Inmentioning

confidence: 94%

Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa

Beltran

Cideciyan

Lewin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

236

260

View full text Add to dashboard Cite

show abstract

“…Retinally colocalized measures of function have often shown both rod and cone loss (Jacobson et al 1997;Lorenz et al 2003;Huang et al 2012) consistent with expression of the RPGR gene product in rod and cone cilia (Hong et al 2000(Hong et al , 2003Roepman et al 2000;Khanna et al 2005;Shu et al 2005). High allelic heterogeneity has been implied as cause for the spectrum of severity and phenotypes encountered between families carrying different RPGR mutations, and there is evidence that genetic modifiers may contribute to intra-familial phenotypic divergence (Keith et al 1991;Walia et al 2008;Ruddle et al 2009;Fahim et al 2011).…”

Section: Retinal Degeneration Phenotype Of Xlrp Patients With Rpgr Mumentioning

confidence: 99%

“…Carrier females with RPGR mutations also show a wide spectrum of retinal disease expression ranging from asymptomatic with normal electrophysiological and psychophysical test results to very severe retina-wide disease (Andreasson et al 1997;Jacobson et al 1997;Weleber et al 1997;Bauer et al 1998;Fishman et al 1998;Flaxel et al 1999;Ayyagari et al 2002;Lorenz et al 2003;Ebenezer et al 2005;Jin et al 2006;Ruddle et al 2009;Thiadens et al 2011). There tends to be significant interocular asymmetry of disease severity in most carriers (Jacobson et al 1989;Weleber et al 1997;Fishman et al 1998;Lorenz et al 2003;Ebenezer et al 2005).…”

Section: Retinal Degeneration Phenotype Of Xlrp Patients With Rpgr Mumentioning

confidence: 99%

“…There tends to be significant interocular asymmetry of disease severity in most carriers (Jacobson et al 1989;Weleber et al 1997;Fishman et al 1998;Lorenz et al 2003;Ebenezer et al 2005). A distinct golden tapetal-like reflex, hypothesized to be located at cone inner segments (Cideciyan and Jacobson 1994), or peripheral photoreceptor outer segments (Berendschot et al 1996), has been variably described in a subset of female carriers of RPGR mutations (Andreasson et al 1997;Jacobson et al 1997;Weleber et al 1997;Bauer et al 1998;Fishman et al 1998;Flaxel et al 1999;Ayyagari et al 2002;Lorenz et al 2003;Ebenezer et al 2005;Jin et al 2006;Ruddle et al 2009;Thiadens et al 2011).…”

Section: Retinal Degeneration Phenotype Of Xlrp Patients With Rpgr Mumentioning

confidence: 99%

See 1 more Smart Citation

Gene Augmentation for X-Linked Retinitis Pigmentosa Caused by Mutations in RPGR

Beltran

Cideciyan

Lewin

et al. 2014

Cold Spring Harbor Perspectives in Medicine

View full text Add to dashboard Cite

“…Polymerase chain reaction products were cloned into the pEASY-Blunt Simple Cloning vector (TransGen Biotech, Beijing, China). The cloned ORF15 insert was then sequenced using primers described previously, 17 as well as additional M13 vector primers.…”

Section: Orf15 Screeningmentioning

confidence: 99%

Identification of false-negative mutations missed by next-generation sequencing in retinitis pigmentosa patients: a complementary approach to clinical genetic diagnostic testing

Huang

et al. 2015

Genetics in Medicine

View full text Add to dashboard Cite

show abstract

RPGR ORF15 genotype and clinical variability of retinal degeneration in an Australian population

Abstract: RPGR ORF15 mutations produce intrafamilial and interfamilial clinical variability with varying degrees of cone degeneration. In an Australian clinic population RPGR ORF15 mutations cause XLCORD in addition to XLRP.

Cited by 25 publications

References 13 publications

Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa

Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa

Gene Augmentation for X-Linked Retinitis Pigmentosa Caused by Mutations in RPGR

Identification of false-negative mutations missed by next-generation sequencing in retinitis pigmentosa patients: a complementary approach to clinical genetic diagnostic testing

Contact Info

Product

Resources

About