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RHO gene

Overview

Gene (OMIM no.)
Function of gene/protein
  • Protein: Rhodopsin
  • Visual pigment in rod photoreceptors
  • Light activation triggers the phototransduction cascade 
Clinical phenotype (with OMIM phenotype no.)
  • Retinitis pigmentosa 4, autosomal dominant or recessive (#613731)Night blindness, congenital stationary, autosomal dominant 1 (#610445)Retinitis punctata albescens (#136880)
Inheritance
  • Autosomal dominant
  • The missense p.Pro23His mutation is a common founder mutation among Americans with European origin; 12-14% of AD-RP cases in the US are due to this variant
  • Only 4 heterozygous variants currently are associated with congenital stationary night blindness (p.G90D, p.T94I, p.A292E and p.A295V)
  • Autosomal recessive
  • Only 4 homozygous RHO variants currently have been reported to cause AR-RP (p.Q28X, p.E150K, p.W161X and p.E249X)
Signs for RP
  • Typical/sectoral RP
Signs for CSNB
  • Normal fundal appearance
Visual functionRetinitis pigmentosa 
  • Inter- and intrafamilial variability in terms of clinical phenotype, age of onset and disease severity
  • Median age of symptom onset in AD-RP is between 1st-2nd decade of life, VA loss from 3rd decade onwards
  • Annual VA decline and VF loss (Goldmann V4e isopter) in AD-RP are 1.8-3.8%/year and 2.6-5.6%/year respectively
  • Sectoral RP patients are relatively asymptomatic and tend to have very slow disease progression
  • Patients with biallelic variants tend to have earlier disease onset and more rapid visual decline

Congenital stationary night blindness 
  • Affected individuals mainly have difficulties navigating in the dark/dimly lit rooms but have preserved cone-mediated vision 
Systemic features
  • No specific associated extraocular features
Key investigations
  • Full field ERG in RP: rod-cone dystrophy initially; unrecordable or significantly reduced rod and cone responses in later stages
  • FAF: Hyper-AF macular ring which constricts over time and peripheral atrophic spots in typical RP phenotype
  • OCT: Parafoveal loss of outer retinal layers corresponding to the border of the hyper-AF macular ring
  • Full field ERG in CSNB: Riggs type; Undetectable rod specific (DA 0.01) ERG response, subnormal a- and b-waves on maximal scotopic ERG (DA 10.0), preserved photopic responses
Molecular diagnosisNext generation sequencing 
  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing
Management
Therapies under research
Further information

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Additional information

Pathogenic mutations in RHO are major causes of AD-RP, accounting for 25-30% of AD-RP cases in White populations[1], while the frequency is much lower among East Asians (2-6.9%)[2-6] and Indians (2%)[7].

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Multimodal imaging

Two images showing the retinal appearance of a patient's right eye. Black pigments are scattered in the lower aspect of the patient's retina along with dense retinal cell death in the same area.
Inferior sectoral retinitis pigmentosa in a patient with autosomal dominant RHO mutation. Bone spicules and RPE atrophy are seen on the inferior retina on wide field colour fundus photography (A). There is generalised retinal degeneration of the inferior retina seen on FAF imaging (B). Two hyperautofluorescent rings are seen, one surrounding the central macula and another larger one surrounding the area of retinal degeneration beyond the vascular arcades (B).
An image showing a small fluorescent ring around the centre of the retina which is a usual finding in patients with retinitis pigmentosa. Another image showing a cross section of the fluorescent ring, demonstrating damaged retinal cells beyond the periphery of the fluorescent ring.
Wide field FAF imaging (A) and SD-OCT scan of the macula (B) of a patient with autosomal dominant RHO mutation. There is a central hyperautofluorescent ring that indicates the border between preserved and diseased outer retina. The central outer retinal layers are relatively preserved, and gradually become thinner with increasing eccentricity on the OCT scan (B).

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References

  1. Verbakel SK, van Huet RAC, Boon CJF, et al. Non-syndromic retinitis pigmentosa. Prog Retin Eye Res. 2018;66:157-186.
  2. Koyanagi Y, Akiyama M, Nishiguchi KM, et al. Genetic characteristics of retinitis pigmentosa in 1204 Japanese patients. J Med Genet. 2019;56(10):662-670.
  3. Kim KJ, Kim C, Bok J, et al. Spectrum of rhodopsin mutations in Korean patients with retinitis pigmentosa. Mol Vis. 2011;17:844-853.
  4. Li S, Xiao X, Wang P, Guo X, Zhang Q. Mutation spectrum and frequency of the RHO gene in 248 Chinese families with retinitis pigmentosa. Biochem Biophys Res Commun. 2010;401(1):42-47.
  5. Chan WM, Yeung KY, Pang CP, et al. Rhodopsin mutations in Chinese patients with retinitis pigmentosa. Br J Ophthalmol. 2001;85(9):1046-1048.
  6. Wang J, Xu D, Zhu T, et al. Identification of two novel RHO mutations in Chinese retinitis pigmentosa patients. Exp Eye Res. 2019;188:107726. 
  7. Gandra M, Anandula V, Authiappan V, et al. Retinitis pigmentosa: mutation analysis of RHO, PRPF31, RP1, and IMPDH1 genes in patients from India. Mol Vis. 2008;14:1105-1113.
  8. Sullivan LS, Bowne SJ, Birch DG, et al. Prevalence of disease-causing mutations in families with autosomal dominant retinitis pigmentosa: a screen of known genes in 200 families. Invest Ophthalmol Vis Sci. 2006;47(7):3052-3064.
  9. Fahim AT, Daiger SP, Weleber RG. Nonsyndromic Retinitis Pigmentosa Overview. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; August 4, 2000.
  10. Dryja TP, McGee TL, Reichel E, et al. A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature. 1990;343(6256):364-366. 
  11. Inglehearn CF, Keen TJ, Bashir R, et al. A completed screen for mutations of the rhodopsin gene in a panel of patients with autosomal dominant retinitis pigmentosa. Hum Mol Genet. 1992;1(1):41-45. 
  12. Xiao T, Xu K, Zhang X, Xie Y, Li Y. Sector Retinitis Pigmentosa caused by mutations of the RHO gene. Eye (Lond). 2019;33(4):592-599.
  13. Nguyen XT, Talib M, van Cauwenbergh C, et al. CLINICAL CHARACTERISTICS AND NATURAL HISTORY OF RHO-ASSOCIATED RETINITIS PIGMENTOSA: A Long-Term Follow-Up Study. Retina. 2020.
  14. Berson EL, Rosner B, Weigel-DiFranco C, Dryja TP, Sandberg MA. Disease progression in patients with dominant retinitis pigmentosa and rhodopsin mutations. Invest Ophthalmol Vis Sci. 2002;43(9):3027-3036.
  15. Rosenfeld PJ, Cowley GS, McGee TL, Sandberg MA, Berson EL, Dryja TP. A null mutation in the rhodopsin gene causes rod photoreceptor dysfunction and autosomal recessive retinitis pigmentosa. Nat Genet. 1992;1(3):209-213.
  16. Kumaramanickavel G, Maw M, Denton MJ, et al. Missense rhodopsin mutation in a family with recessive RP. Nat Genet. 1994;8(1):10-11. 
  17. Greenberg J, Roberts L, Ramesar R. A rare homozygous rhodopsin splice-site mutation: the issue of when and whether to offer presymptomatic testing. Ophthalmic Genet. 2003;24(4):225-232. 
  18. Azam M, Khan MI, Gal A, et al. A homozygous p.Glu150Lys mutation in the opsin gene of two Pakistani families with autosomal recessive retinitis pigmentosa. Mol Vis. 2009;15:2526-2534.
  19. Zhang N, Kolesnikov AV, Jastrzebska B, et al. Autosomal recessive retinitis pigmentosa E150K opsin mice exhibit photoreceptor disorganization. J Clin Invest. 2013;123(1):121-137.
  20. Kartasasmita A, Fujiki K, Iskandar E, Sovani I, Fujimaki T, Murakami A. A novel nonsense mutation in rhodopsin gene in two Indonesian families with autosomal recessive retinitis pigmentosa. Ophthalmic Genet. 2011;32(1):57-63.
  21. Dryja TP, Berson EL, Rao VR, Oprian DD. Heterozygous missense mutation in the rhodopsin gene as a cause of congenital stationary night blindness. Nat Genet. 1993;4(3):280-283.
  22. Sieving PA, Richards JE, Naarendorp F, Bingham EL, Scott K, Alpern M. Dark-light: model for night blindness from the human rhodopsin Gly-90–>Asp mutation. Proc Natl Acad Sci U S A. 1995;92(3):880-884. 
  23. al-Jandal N, Farrar GJ, Kiang AS, et al. A novel mutation within the rhodopsin gene (Thr-94-Ile) causing autosomal dominant congenital stationary night blindness. Hum Mutat. 1999;13(1):75-81.
  24. Zeitz C, Gross AK, Leifert D, et al. Identification and functional characterization of a novel rhodopsin mutation associated with autosomal dominant CSNB. Invest Ophthalmol Vis Sci. 2008;49(9):4105-4114.
  25. McAlear SD, Kraft TW, Gross AK. 1 rhodopsin mutations in congenital night blindness. Adv Exp Med Biol. 2010;664:263-272. 

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Updated on December 15, 2021

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