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RDH12 gene

Overview

Gene (OMIM No.)
Function of gene/protein
  • Protein: retinal dehydrogenase 12
  • Expressed in the inner segments of photoreceptors
  • Reduces all-trans-retinal to all-trans-retinol for regeneration of visual pigment in the visual cycle
  • Reduce production of toxic N-retinylidene-N-retinylethanolamine (A2E)
  • Protection against toxic lipid peroxidation products
Clinical phenotype
(OMIM phenotype no.)
Inheritance
  • Autosomal recessive
  • Autosomal dominant (rare)
Signs for LCA/EOSRD
  • Nyctalopia
  • Pendular nystagmus
  • Early-onset posterior subcapsular cataract
  • Dyschromatopsia
  • Range of pigmentary changes in the retina (minimal to dense pigment migration in the mid-periphery, para-arteriolar sparing of the RPE)
  • Early onset maculopathy (RPE depigmentation, yellowish foveal centre with RPE mottling, bull’s eye maculopathy, bone-spicule pigmentation, atrophy)
Signs for RP
  • Typical RP features
  • Macula sparing in contrast to AR phenotype
Visual functionAutosomal recessive RDH12-retinopathy
  • Early-onset visual loss, usually in the 1st decade
  • VF and VA can be variable (6/9 or 0.18 LogMAR to NPL) at presentation
  • Progressive VF and VA loss during adolescence
Autosomal dominant RDH12-retinopathy
  • Late-onset (2nd-5th decade) mild RP
  • BCVA 6/6 to 6/9 on presentation
  • Some maintain good VA (6/7.5) until the 8th decade
Systemic features
  • No extraocular anomalies reported
Key investigations
  • ERG: absent responses/rod-cone dystrophy
  • FAF: Radial hypo-AF regions in areas of RPE atrophy with a surrounding band of hyper-AF; peripapillary sparing
  • OCT: Outer retinal lamination visible near the optic disc which gradually disappears towards the fovea, corresponding to early onset macular involvement
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing
ManagementOcular
Therapies under research
Further information

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Additional information

While more than eighty RDH12 variants are associated with autosomal recessive retinopathy[1], two variants were reported to be associated with autosomal dominant cases: c.776delG p.(Glu260Argfs*18) was identified in nineteen affected family members[9] and c.759del p.(Phe254Leufs*24) was described in two unrelated affected patients.[10]

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Multimodal imaging

A patient with RDH12-LCA. There is dense RPE hyperpigmentation in the mid-periphery with macular atrophy (A). The FAF appearance (B) is typical of RDH12-retinopathy showing areas of hypo-AF corresponding to areas with RPE atrophy, which is surrounded by a band of hyper-AF. Macular OCT (C) shows outer retinal and RPE atrophy.
RDH12-LCA patient with dense RPE hyperpigmentation in the mid-periphery and macular atrophy (A). There is sparing of the peripapillary AF which can be observed in RDH12-retinopathy (B).

References

  1.  Sarkar H, Moosajee M. Retinol dehydrogenase 12 (RDH12): Role in vision, retinal disease and future perspectives. Exp Eye Res. 2019 Nov;188:107793
  2.  Zou X, Fu Q, Fang S, Li H, Ge Z, Yang L, et al. PHENOTYPIC VARIABILITY OF RECESSIVE RDH12-ASSOCIATED RETINAL DYSTROPHY: Retina. 2019 Oct;39(10):2040–52
  3.  Fahim AT, Bouzia Z, Branham KH, Kumaran N, Vargas ME, Feathers KL, et al. Detailed clinical characterisation, unique features and natural history of autosomal recessive RDH12 -associated retinal degeneration. Br J Ophthalmol. 2019 Apr 12;bjophthalmol-2018-313580
  4.  Aleman TS, Uyhazi KE, Serrano LW, Vasireddy V, Bowman SJ, Ammar MJ, et al. RDH12 Mutations Cause a Severe Retinal Degeneration With Relatively Spared Rod Function. Investig Opthalmology Vis Sci. 2018 Oct 1;59(12):5225
  5.  Sodi A, Caputo R, Passerini I, Maria Bacci G, Menchini U. Novel RDH12 sequence variations in Leber congenital amaurosis. J Am Assoc Pediatr Ophthalmol Strabismus. 2010 Aug;14(4):349–51
  6.  Janecke AR, Thompson DA, Utermann G, Becker C, Hübner CA, Schmid E, et al. Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset severe retinal dystrophy. Nat Genet. 2004 Aug;36(8):850–4
  7.  Aït-Ali N, Fridlich R, Millet-Puel G, Clérin E, Delalande F, Jaillard C, et al. Rod-Derived Cone Viability Factor Promotes Cone Survival by Stimulating Aerobic Glycolysis. Cell. 2015 May;161(4):817–32
  8.  Byrne LC, Dalkara D, Luna G, Fisher SK, Clérin E, Sahel J-A, et al. Viral-mediated RdCVF and RdCVFL expression protects cone and rod photoreceptors in retinal degeneration. J Clin Invest. 2015 Jan 2;125(1):105–16
  9.  Fingert JH. Association of a Novel Mutation in the Retinol Dehydrogenase 12 (RDH12) Gene With Autosomal Dominant Retinitis Pigmentosa. Arch Ophthalmol. 2008 Sep 8;126(9):1301
  10.  Sarkar H, Dubis AM, Downes S, Moosajee M. Novel Heterozygous Deletion in Retinol Dehydrogenase 12 (RDH12) Causes Familial Autosomal Dominant Retinitis Pigmentosa. Front Genet. 2020;11:335

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Updated on November 30, 2020
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