RPGR gene


Gene (OMIM No.)
Function of gene/protein
  • Protein: Retinitis pigmentosa GTPase regulator
  • Multiple isoforms due to alternative splicing
  • The RPGRORF15 isoform is most highly expressed in the retina
  • Facilitates the transport of opsins from the photoreceptor inner segment to the outer segment via the connecting cilia
  • RPGRORF15 transcript consists of exon 1-14 and ORF15 exon
  • The ORF15 exon has an unusual repetitive sequence which makes it mutation “hot-spot”
Clinical phenotype
(OMIM phenotype no.)
  • X-linked recessive
Signs for X-linked RPMale patients
  • Vessel attenuation
  • Bone-spicule pigmentations in the mid-periphery
  • Variable macular involvement (RPE depigmentation, bull’s eye maculopathy, profound atrophy)
  • Optic disc pallor
  • Optic disc drusen may be observed in minority of cases
  • Posterior sub-capsular cataract
  • High myopia (<-6.00D)
Female carriers
  • Variable appearance ranging from no abnormalities, tapetal-like reflex (most common) to patchy/diffuse pigmentary changes and degeneration with variable macular involvement
  • Intraindividual asymmetry may be observed
  • High myopia (<-6.00D)
Signs for cone/cone-rod dystrophy
  • Early macular involvement (RPE alteration, bull’s eye maculopathy, outer retinal and RPE atrophy)
  • Variable amount of bone-spicule pigmentation
  • Vessel attenuation
  • High myopia (<-6.00D)
Signs for macular degeneration
  • Predominant macular atrophy
  • 1 patient also had peripheral retinal degeneration similar to RP changes
  • Myopia (-3.00 to -13.00D)
Visual functionX-linked RP
  • Early disease onset (usually during 1st decade of life) which is rapidly progressive
  • May reach blindness by the 4th decade
  • Progressive VF and VA loss from 2nd decade of life
  • Peripheral VF loss at a rate of 6.6%/year
  • BCVA declines at a rate of 3-5%/year but the rate is faster if associated with high myopia (<-6.00D) and more advanced age (after 20 years)
X-linked cone/cone-rod dystrophy
  • Onset of central vision loss from 2nd to 4th decade of life
  • Dyschromatopsia
  • Faster rate of BCVA decline than RP and is accelerated with high myopia and after the age of 50
  • 55% of patients are certified blind by age of 40 based on WHO BCVA criteria (Snellen 6/120 or worse)
  • Rod dysfunction early in the disease course in CORD
  • Peripheral VF loss at a rate of 2.1%/year
Macular degeneration, X-linked atrophic
  • Rapidly progressive central vision loss (BCVA 6/60 or worse in all patients)
  • Preserved peripheral vision
Female carriers
  • Range of severity due to varying degrees of non-random (skewed) X-inactivation
  • Most carriers are asymptomatic/mildly affected
  • Some can be as severely affected as male patients
  • Later age of symptom onset
  • Myopia is common and associated with worse BCVA
  • Majority do not deteriorate to level of legal blindness
Systemic featuresRetinitis pigmentosa, X-linked, and sinorespiratory infections, with or without deafness:
  • Chronic recurrent respiratory tract infections
  • Bronchiectasis
  • Sensorineural hearing loss
  • Recurrent ear infections
Key investigations
  • Full field and pattern ERG
  • FAF in male RP: Central macular hyper-AF ring which constricts over time; gradually progresses to areas with granular hypo-AF (outside arcade > posterior pole initially) which eventually leads to near-complete pan-retinal absence of AF
  • The ring demarcates a transition zone from a relatively preserved outer retina to a more degenerated and thinned retina
  • OCT in RP: Progressive shortening of foveal ellipsoid zone length at 248 µm/year and outer retinal thinning
  • FAF in cone/cone-rod dystrophy: Hyper-AF ring around a hypo-AF macula
  • Opposite pattern to RP where outer retinal attenuation and thinning are observed on OCT within the ring
  • The ring gradually enlarges over time with disease progression
  • FAF in female carriers: Radial pattern of different AF or mottled hypo-AF changes in areas that appear unaffected on fundoscopy
  • Systemic assessment may be required if extraocular features are present
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing
  • Multidisciplinary approach
Therapies under research
Further information

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Additional information

Pathogenic variants in RPGR account for 70-80% of X-linked RP cases and approximately 10% of total RP cases overall.[4,15-17] There is considerable intrafamilial phenotypic variability where the same genotype can cause both cone-rod dystrophy and RP phenotypes in different members of the same family.[8]

The highly repetitive ORF15 exon is a mutation “hot-spot” where most reported cone/cone-rod dystrophy variants and more than 50% of XL-RP variants are located.[4,10] A genotype-phenotype relationship can be observed:

  • Most cone/cone-rod dystrophy variants are located towards the 3’ end of the ORF15 exon while those causing RP are located towards the 5’ end[19-22]
  • Some studies have observed that patients harbouring variants in ORF15 display a milder RP phenotype compared to those with variants in exons 1-14, while other studies have suggested the contrary[8,15,18,21,22]

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Multimodal imaging

Retinitis pigmentosa

A RP patient with hemizygous RPGR mutation. Wide field fundus photograph (A) shows diffuse bone-spicule hyperpigmentation and RPE atrophy in the mid-periphery, correlating to the findings on FAF imaging (B). There is a central area of hypoautofluorescence surrounded by a ring of hyperautofluorescence. A smaller hyperautofluorescent area is seen centrally.
OCT scan through the macula of the same patient showing marked outer retinal and RPE atrophy except for a small area at the fovea. Outer retinal tubulations are also seen.

Cone dystrophy

The retina of a patient with cone dystrophy due to mutation in the RPGR gene. The retina looks relatively normal apart from the macula which looks degenerated.
A hemizygous RPGR male with primarily cone dysfunction. Wide field colour fundus photograph (A) shows central macular atrophy with vessel attenuation. FAF imaging (B) shows the area of central macular atrophy clearly, delineated by an hyperautofluorescent ring. The periphery is relatively preserved.
The central hyperautofluorescent ring seen in the FAF image above represents the border between preserved and atrophic retina.

Female carrier

Wide field colour fundus photograph (A) and FAF imaging (B) of a female carrier. A characteristic tapetal-like reflex is visible on A, which appears a radial patterns of increased and decreased autofluorescence.

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  1.  Megaw RD, Soares DC, Wright AF. RPGR: Its role in photoreceptor physiology, human disease, and future therapies. Exp Eye Res. 2015;138:32-41
  2.  Kirschner R, Rosenberg T, Schultz-Heienbrok R, et al. RPGR transcription studies in mouse and human tissues reveal a retina-specific isoform that is disrupted in a patient with X-linked retinitis pigmentosa. Hum Mol Genet. 1999;8(8):1571-1578
  3.  Hosch J, Lorenz B, Stieger K. RPGR: role in the photoreceptor cilium, human retinal disease, and gene therapy. Ophthalmic Genet. 2011;32(1):1-11
  4.  Vervoort R, Lennon A, Bird AC, et al. Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa. Nat Genet. 2000;25(4):462-466
  5.  Kurata K, Hosono K, Hayashi T, et al. X-linked Retinitis Pigmentosa in Japan: Clinical and Genetic Findings in Male Patients and Female Carriers. Int J Mol Sci. 2019;20(6)
  6.  Koenekoop RK, Loyer M, Hand CK, et al. Novel RPGR mutations with distinct retinitis pigmentosa phenotypes in French-Canadian families. Am J Ophthalmol. 2003;136(4):678-687
  7.  Nguyen XT, Talib M, van Schooneveld MJ, et al. RPGR-Associated Dystrophies: Clinical, Genetic, and Histopathological Features. Int J Mol Sci. 2020;21(3)
  8.  Talib M, van Schooneveld MJ, Thiadens AA, et al. CLINICAL AND GENETIC CHARACTERISTICS OF MALE PATIENTS WITH RPGR-ASSOCIATED RETINAL DYSTROPHIES: A Long-Term Follow-up Study. Retina. 2019;39(6):1186-1199
  9.  Talib M, van Schooneveld MJ, Van Cauwenbergh C, et al. The Spectrum of Structural and Functional Abnormalities in Female Carriers of Pathogenic Variants in the RPGR Gene. Invest Ophthalmol Vis Sci. 2018;59(10):4123-4133
  10.  Tee JJ, Smith AJ, Hardcastle AJ, Michaelides M. RPGR-associated retinopathy: clinical features, molecular genetics, animal models and therapeutic options. Br J Ophthalmol. 2016;100(8):1022-1027
  11.  Comander J, Weigel-DiFranco C, Sandberg MA, Berson EL. Visual Function in Carriers of X-Linked Retinitis Pigmentosa. Ophthalmology. 2015;122(9):1899-1906
  12.  Moore A, Escudier E, Roger G, et al. RPGR is mutated in patients with a complex X linked phenotype combining primary ciliary dyskinesia and retinitis pigmentosa. J Med Genet. 2006;43(4):326-333
  13.  Iannaccone A, Breuer DK, Wang XF, et al. Clinical and immunohistochemical evidence for an X linked retinitis pigmentosa syndrome with recurrent infections and hearing loss in association with an RPGR mutation. J Med Genet. 2003;40(11):e118
  14.  Birch DG, Locke KG, Wen Y, Locke KI, Hoffman DR, Hood DC. Spectral-domain optical coherence tomography measures of outer segment layer progression in patients with X-linked retinitis pigmentosa. JAMA Ophthalmol. 2013;131(9):1143-1150
  15.  Sharon D, Sandberg MA, Rabe VW, Stillberger M, Dryja TP, Berson EL. RP2 and RPGR mutations and clinical correlations in patients with X-linked retinitis pigmentosa. Am J Hum Genet. 2003;73(5):1131-1146
  16.  Shu X, Black GC, Rice JM, et al. RPGR mutation analysis and disease: an update. Hum Mutat. 2007;28(4):322-328
  17.  Pelletier V, Jambou M, Delphin N, et al. Comprehensive survey of mutations in RP2 and RPGR in patients affected with distinct retinal dystrophies: genotype-phenotype correlations and impact on genetic counseling. Hum Mutat. 2007;28(1):81-91
  18.  Fahim AT, Bowne SJ, Sullivan LS, et al. Allelic heterogeneity and genetic modifier loci contribute to clinical variation in males with X-linked retinitis pigmentosa due to RPGR mutations. PLoS One. 2011;6(8):e23021
  19.  Ebenezer ND, Michaelides M, Jenkins SA, et al. Identification of novel RPGR ORF15 mutations in X-linked progressive cone-rod dystrophy (XLCORD) families. Invest Ophthalmol Vis Sci. 2005;46(6):1891-1898
  20.  Demirci FY, Rigatti BW, Wen G, et al. X-linked cone-rod dystrophy (locus COD1): identification of mutations in RPGR exon ORF15. Am J Hum Genet. 2002;70(4):1049-1053
  21.  Yang L, Yin X, Feng L, et al. Novel mutations of RPGR in Chinese retinitis pigmentosa patients and the genotype-phenotype correlation. PLoS One. 2014;9(1):e85752
  22.  Andréasson S, Breuer DK, Eksandh L, et al. Clinical studies of X-linked retinitis pigmentosa in three Swedish families with newly identified mutations in the RP2 and RPGR-ORF15 genes. Ophthalmic Genet. 2003;24(4):215-223

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Updated on May 3, 2021
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