EYS gene

Overview

Gene (OMIM No.)
Function of gene/protein
  • Protein: Eyes shut homolog
  • Extracellular matrix protein located in the connecting cilium of photoreceptors
  • Exact function not clearly understood
  • Maintaining ciliary pocket lumen and photoreceptor structure hypothesised
Clinical phenotype
(OMIM phenotype no.)
Inheritance
  • Autosomal recessive
Signs for AR-RP
  • Optic disc pallor
  • Vessel attenuation
  • Severe extramacular retinal atrophy with bone-spicule pigmentations in the mid-periphery
  • Increase in pigmentation density over time
  • Macular abnormalities are rarely observed
  • Posterior sub-capsular cataract
Visual function
  • Age of onset variable, ranging from 13 to after 50 years old
  • Rapid peripheral VF loss (mean rate of decline with a V4e target on kinetic perimetry is 23%/year)
  • Relatively preserved VA early in the disease course with slow progression
  • BCVA at least 6/9 in the 1st decade and progressively deteriorate at 5.7%/year (0.024 LogMAR/year)
  • Rate of VF and VA loss more rapid than AR-RP caused by USH2A and MAK mutations
  • Patients with two null alleles tend to experience faster visual decline than those harbouring only one null allele
Systemic features
  • No extraocular features reported
Key investigations
  • Full field ERG: rod-cone dystrophy initially; unrecordable or significantly reduced rod and cone responses in later stages
  • FAF: Relatively preserved macular AF surrounded by areas of hypo-AF corresponding to RPE atrophy
  • OCT: Relatively preserved foveal outer retinal layers while there is progressive outer retinal thinning and degeneration parafoveally
  • EZ width is a reliable marker for disease progression; progressive shortening of foveal EZ width and ONL thinning over time
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing
Management
Therapies under research
  • None in clinical trials at present
  • Natural history study Pro-EYS (NCT 04127006)
Further information

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Additional information

Pathogenic mutations in EYS is a major cause of AR-RP, accounting for 5-16% of AR-RP cases in non-Finnish Caucasians and up to 30.9% among Japanese.[1-8] The p.Ile1451Profs*3 variant is the most frequently reported variant in Caucasians while the p.Ser1653Lysfs*2 variant is the most common among Japanese followed by the p.Tyr2935*variant.[3]

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Multimodal imaging

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References

  1.  Birtel J, Gliem M, Mangold E, et al. Next-generation sequencing identifies unexpected genotype-phenotype correlations in patients with retinitis pigmentosa. PLoS One. 2018;13(12):e0207958
  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.  Messchaert M, Haer-Wigman L, Khan MI, Cremers FPM, Collin RWJ. EYS mutation update: In silico assessment of 271 reported and 26 novel variants in patients with retinitis pigmentosa. Hum Mutat. 2018;39(2):177-186
  4.  Ge Z, Bowles K, Goetz K, et al. NGS-based Molecular diagnosis of 105 eyeGENE((R)) probands with Retinitis Pigmentosa. Sci Rep. 2015;5:18287
  5.  Littink KW, van den Born LI, Koenekoop RK, et al. Mutations in the EYS gene account for approximately 5% of autosomal recessive retinitis pigmentosa and cause a fairly homogeneous phenotype. Ophthalmology. 2010;117(10):2026-2033, 2033.e2021-2027
  6.  Barragán I, Borrego S, Pieras JI, et al. Mutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa. Hum Mutat. 2010;31(11):E1772-1800
  7.  Abd El-Aziz MM, O’Driscoll CA, Kaye RS, et al. Identification of novel mutations in the ortholog of Drosophila eyes shut gene (EYS) causing autosomal recessive retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2010;51(8):4266-4272
  8.  Mucciolo DP, Sodi A, Passerini I, et al. Fundus phenotype in retinitis pigmentosa associated with EYS mutations. Ophthalmic Genet. 2018;39(5):589-602
  9.  Abd El-Aziz MM, Barragan I, O’Driscoll CA, et al. EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa. Nat Genet. 2008;40(11):1285-1287
  10.  Husain N, Pellikka M, Hong H, et al. The agrin/perlecan-related protein eyes shut is essential for epithelial lumen formation in the Drosophila retina. Dev Cell. 2006;11(4):483-493
  11.  Yu M, Liu Y, Li J, et al. Eyes shut homolog is required for maintaining the ciliary pocket and survival of photoreceptors in zebrafish. Biol Open. 2016;5(11):1662-1673
  12.  McGuigan DB, Heon E, Cideciyan AV, et al. EYS Mutations Causing Autosomal Recessive Retinitis Pigmentosa: Changes of Retinal Structure and Function with Disease Progression. Genes (Basel). 2017;8(7)
  13.  Iwanami M, Oshikawa M, Nishida T, Nakadomari S, Kato S. High prevalence of mutations in the EYS gene in Japanese patients with autosomal recessive retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2012;53(2):1033-1040
  14.  Miyata M, Ogino K, Gotoh N, et al. Inner segment ellipsoid band length is a prognostic factor in retinitis pigmentosa associated with EYS mutations: 5-year observation of retinal structure. Eye (Lond). 2016;30(12):1588-1592
  15.  Zahid S, Branham K, Schlegel D, et al. Retinal Dystrophy Gene Atlas. Springer; 2018

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Updated on November 30, 2020

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