RPE65 gene


Gene (OMIM no.)
Function of gene/protein
  • Protein: retinoid isomerase
  • Recycling of 11-cis-retinal in the visual cycle for phototransduction through isomerisation of all-trans-retinyl esters 
  • Cone photoreceptors are less affected initially compared to rods due to an alternative supply of 11-cis-retinal
Clinical phenotype
(OMIM phenotype no.)
  • Autosomal recessive
  • Autosomal dominant (rarely)
Signs for LCA/EOSRD
  • Early onset visual impairment (0.4 LogMAR to PL)
  • Roving nystagmus
  • Poor visual pursuit
  • Milder phenotype in EOSRD with minimal/no nystagmus due to relatively preserved cone function initially
  • Blonde fundus with minimal pigmentation
  • RPE mottling
  • Deep white punctate lesions in the periphery
  • Sparse bone spicule pigmentation in the periphery in later stages (uncommon)
  • Macular atrophy
Signs for AD-RP
  • Rare disease phenotype
  • Nummular pigmentation in mid-periphery during early stages
  • Diffuse chorioretinal atrophy similar to choroideremia in advanced stages
Visual functionAutosomal recessive RPE65 retinopathy: 
  • Early onset nyctalopia is a common presenting feature
  • Reduced VA but may be able to function normally in bright conditions early on
  • Progressive VF and VA loss after 1st decade of life, with most certified blind by the 4th decade
Autosomal dominant RPE65 retinopathy: 
  • Later onset of symptoms (2nd to 5th decade) with slower rate of VF and VA decline
  • Some have relatively preserved VA despite advanced chorioretinal degeneration
Systemic features
  • No extraocular features reported
Key investigations
  • ERG: absent responses/severe rod-cone dystrophy
  • FAF: reduced/absent AF
  • OCT: Preserved foveal ONL but thinned parafoveally along with outer retinal layer disruption in LCA/EOSRD cases
Molecular diagnosisNext generation sequencing: 
  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing
Therapies under research
Further information

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Multimodal imaging

There is marked degeneration in the far periphery of the retina, appearing white. This is accompanied by some black pigments distributed throughout.
Multimodal imaging of a 28 year old patient with RPE65-LCA. Colour fundal photography (A) shows deep white punctate lesions and atrophy in the periphery but relatively preserved posterior pole with sparse bone-spicule pigments. There is absent AF (B) and SD-OCT (C) shows preserved foveal lamination but outer retinal and RPE atrophy parafoveally.

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  1.  Morimura H, Fishman GA, Grover SA, Fulton AB, Berson EL, Dryja TP. Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis. Proc Natl Acad Sci U S A. 1998;95(6):3088-3093.
  2.  Chung DC, Bertelsen M, Lorenz B, et al. The Natural History of Inherited Retinal Dystrophy Due to Biallelic Mutations in the RPE65 Gene. Am J Ophthalmol. 2019;199:58-70.
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  6.  Hull S, Holder GE, Robson AG, et al. Preserved visual function in retinal dystrophy due to hypomorphic RPE65 mutations. Br J Ophthalmol. 2016;100(11):1499-1505.
  7.  Bowne SJ, Humphries MM, Sullivan LS, et al. A dominant mutation in RPE65 identified by whole-exome sequencing causes retinitis pigmentosa with choroidal involvement. Eur J Hum Genet. 2011;19(10):1074-1081.
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  9.  Magliyah M, Saifaldein AA, Schatz P. Late presentation of RPE65 retinopathy in three siblings. Doc Ophthalmol. 2020;140(3):289-297.
  10.  Kumaran N, Moore AT, Weleber RG, Michaelides M. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions. Br J Ophthalmol. 2017;101(9):1147-1154
  11.  Lorenz B, Wabbels B, Wegscheider E, Hamel CP, Drexler W, Preising MN. Lack of fundus autofluorescence to 488 nanometers from childhood on in patients with early-onset severe retinal dystrophy associated with mutations in RPE65. Ophthalmology. 2004;111(8):1585-1594
  12.  Jacobson SG, Cideciyan AV, Huang WC, et al. Leber Congenital Amaurosis: Genotypes and Retinal Structure Phenotypes. Adv Exp Med Biol. 2016;854:169-175.
  13.  Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390(10097):849-860

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Updated on November 30, 2020
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