Identification of OPN1LW Exon 3 Variants Impairing Red-Cone Function in Color Vision Deficiency
DOI:
https://doi.org/10.14500/aro.12480Keywords:
Color vision deficiency, Exon 3, Nucleotide variants, OPN1LW gene, PolyPhen-2, SIFTAbstract
The most common form of inherited color blindness is red-green color vision deficiency (CVD), which is frequently caused by mutations in the X-linked OPN1LW gene. Red cone malfunction is linked to mutations in exon 3 of this gene. In this study, the Ishihara test was used to evaluate the color vision of 1500 Kurdish students, ages 13–18. Polymerase chain reaction amplification and Sanger sequencing of OPN1LW exon 3 were performed on 50 students who had been diagnosed with protanopia or protanomaly. Variants (nucleotide changes) were analyzed using Geneious Prime® software. Functional impact of variants was predicted using PolyPhen-2 and SIFT. The study found 30 different nucleotide variations, comprising 63.3% missense mutations, 23.3% silent mutations, and 13.3% frameshift mutations. The most common variants were found c.30G>A (p. Arg10Arg), c.106T>C (p. His35Pro), and c.161_162insG (p. Asp54Gly). SIFT found (57.8%) of variations as deleterious (scoring ≤0.05), but PolyPhen-2 assessed (63.1%) as potentially damaging (score >0.9). ABO blood type was unrelated to CVD risk, although consanguinity and family history were strongly linked to CVD risk. Our study revealed that people with red-green CVD have frequent and possibly harmful mutations in exon 3 of OPN1LW. These results may aid in the molecular characterization of CVD in the Kurdish population and could help develop future diagnostic and treatment approaches.
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Aboshiha, J., Dubis, A.M., Carroll, J., Hardcastle, A.J., and Michaelides, M., 2016. The cone dysfunction syndromes. British Journal of Ophthalmology, 100, pp.115‑121. DOI: https://doi.org/10.1136/bjophthalmol-2014-306505
Adzhubei, I.A., Schmidt, S., Peshkin, L., Ramensky, V.E., Gerasimova, A., Bork, P., Kondrashov, A.S., and Sunyaev, S.R., 2010. A method and server for predicting damaging missense mutations. Nature Methods, 7, pp.248-249. DOI: https://doi.org/10.1038/nmeth0410-248
Akhtar, M.S., Aslamkhan, M., Zar, M.S., Hanif, A., and Haris, A.R., 2019. Dichromacy: Color vision impairment and consanguinity in heterogenous population of Pakistan. The International Journal of Frontier Sciences, 3, pp.41‑56. DOI: https://doi.org/10.37978/tijfs.v3i1.47
Alam, F., Salih, A.E., Elsherif, M., Yetisen, A.K., and Butt, H., 2022. 3D printed contact lenses for the management of color blindness. Additive Manufacturing, 49, pp.102464. DOI: https://doi.org/10.1016/j.addma.2021.102464
Alnahedh, T., Alnahedh, A., Alhawas, A., Marghlani, L., Al Harbi, W., and Alhadlaq, O.S., 2025. The prevalence of color vision deficiency in medical students at King Saud bin Abdulaziz university for health sciences. The Open Ophthalmology Journal, 19, p. e18743641353155. DOI: https://doi.org/10.2174/0118743641353155250131105457
Asadi, S., 2023. The role of mutations on Gene NF1 in neurofibromatosis type 1 syndrome. International Journal of clinical and Medical Case Reports, 2, pp. 1‑6.
Asenjo, A.B., Rim, J., and Oprian, D.D., 1994. Molecular determinants of human red/green color discrimination. Neuron, 12, pp.1131‑1138. DOI: https://doi.org/10.1016/0896-6273(94)90320-4
Atilano, S.R., Kenney, M.C., Briscoe, A.D., and Jameson, K.A., 2020. A twostep method for identifying photopigment opsin and rhodopsin gene sequences underlying human color vision phenotypes. Molecular Vision, 26, p.158.
Balachandran, P., and Beck, C.R., 2020. Structural variant identification and characterization. Chromosome Research, 28, pp.31-47. DOI: https://doi.org/10.1007/s10577-019-09623-z
Basta, M., and Pandya, A.M., 2020. Genetics, X‑Linked Inheritance. StatPearls Birch, J., 1997. Efficiency of the Ishihara test for identifying red-green colour deficiency. Ophthalmic and Physiological Optics, 17, pp.403-408. DOI: https://doi.org/10.1016/S0275-5408(97)00022-7
Birch, J., 2012. Worldwide prevalence of red-green color deficiency. Journal of the Optical Society of America A, 29, pp.313-320. DOI: https://doi.org/10.1364/JOSAA.29.000313
Buena-Atienza, E., Rüther, K., Baumann, B., Bergholz, R., Birch, D., De Baere, E., Dollfus, H., Greally, M.T., Gustavsson, P., and Hamel, C.P., 2016. De novo intrachromosomal gene conversion from OPN1MW to OPN1LW in the male germline results in blue cone monochromacy. Scientific Reports, 6, p.28253. DOI: https://doi.org/10.1038/srep28253
Cai, Z.X., 2023. Link color blind: A systematic review of congenital color vision deficiency cognitively and neurologically. SHS Web of Conferences, 180, p.03015. DOI: https://doi.org/10.1051/shsconf/202318003015
Davidoff, C., 2015. Cone Opsin Gene Variants in Color Blindness and other Vision Disorders. University of Washington, Washington, DC. Dong, C., Wei, P., Jian, X., Gibbs, R., Boerwinkle, E., Wang, K., and Liu, X., 2015. Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies. Human Molecular Genetics, 24, pp.2125-2137. DOI: https://doi.org/10.1093/hmg/ddu733
Ebrahim, N., Shaker, I.A., and Kadhir, A., 2016. Prevalence of color vision deficiency (CVD) and ABO blood groups in Kannur district of Kerala, India. International Journal of Bioassays, 5, pp.4760-4763. DOI: https://doi.org/10.21746/ijbio.2016.01.0011
Gardner, J.C., Liew, G., Quan, Y.H., Ermetal, B., Ueyama, H., Davidson, A.E., Schwarz, N., Kanuga, N., Chana, R., and Maher, E.R., 2014. Three different cone opsin gene array mutational mechanisms with genotype-phenotype correlation and functional investigation of cone opsin variants. Human Mutation, 35, pp.1354‑1362. DOI: https://doi.org/10.1002/humu.22679
Gocuk, S.A., Lancaster, J., Su, S., Jolly, J.K., Edwards, T.L., Hickey, D.G., Ritchie, M.E., Blewitt, M.E., Ayton, l.N., and Gouil, Q., 2024. Measuring X-chromosome inactivation skew for X-linked diseases with adaptive nanopore sequencing. Genome Research, 34, pp.1954-1965. DOI: https://doi.org/10.1101/gr.279396.124
Greenwald, S.H., Kuchenbecker, J.A., Rowlan, J.S., Neitz, J., and Neitz, M., 2017. Role of a dual splicing and amino acid code in Myopia, cone dysfunction and cone dystrophy associated with L/M opsin interchange mutations. Translational Vision Science and Technology, 6, p.2. DOI: https://doi.org/10.1167/tvst.6.3.2
Grimm, D.G., Azencott, C.A., Aicheler, F., Gieraths, U., Macarthur, D.G., Samocha, K.E., Cooper, D.N., Stenson, P.D., Daly, M.J., and Smoller, J.W., 2015. The evaluation of tools used to predict the impact of missense variants is hindered by two types of circularity. Human Mutation, 36, pp.513‑523. DOI: https://doi.org/10.1002/humu.22768
Gudeta, T.B., and Asrat, T., 2024. Prevalence and genotypic frequency of color vision defects among primary schoolchildren in Adama Town, Eastern Ethiopia. BMC Pediatrics, 24, p.72. DOI: https://doi.org/10.1186/s12887-024-04529-0
Haer-Wigman, L., Den Ouden, A., Van Genderen, M.M., Kroes, H.Y., Verheij, J., Smailhodzic, D., Hoekstra, A.S., Vijzelaar, R., Blom, J., and Derks, R., 2022.
Diagnostic analysis of the highly complex OPN1LW/OPN1MW gene cluster using long-read sequencing and MLPA. NPJ Genomic Medicine, 7, p.65.
Haim, M., Fledelius, H.C., and Skarsholm, D., 1988. X‐linked myopia in danish family. Acta Ophthalmologica, 66, pp.450‑456. DOI: https://doi.org/10.1111/j.1755-3768.1988.tb04039.x
Hussein, A.J., and Al-Dabbagh, S.A., 2022. Prevalence of color vision deficiency among primary school pupils in Duhok city, Kurdistan Region, Iraq. AMJ (Advanced Medical Journal), 7, pp.11-16. DOI: https://doi.org/10.56056/amj.2022.153
Jafarzadehpur, E., Hashemi, H., Emamian, M.H., Khabazkhoob, M., Mehravaran, S., Shariati, M., and Fotouhi, A., 2014. Color vision deficiency in a middle-aged population: The Shahroud Eye Study. International Ophthalmology, 34, pp.1067-1074. DOI: https://doi.org/10.1007/s10792-014-9911-2
Jaganathan, K., Panagiotopoulou, S.K., Mcrae, J.F., Darbandi, S.F., Knowles, D., Li, Y.I., Kosmicki, J.A., Arbelaez, J., Cui, W., and Schwartz, G.B., 2019. Predicting splicing from primary sequence with deep learning. Cell, 176, pp.535‑548.e24. DOI: https://doi.org/10.1016/j.cell.2018.12.015
Karim, K.J., and Saleem, M.A., 2013. Prevalence of congenital red-green color vision defects among various ethnic groups of students in Erbil City. Jordan Journal of Biological Sciences, 6, pp.235‑238. DOI: https://doi.org/10.12816/0001540
Kim, J.M., Altenbach, C., Kono, M., Oprian, D.D., Hubbell, W.L., and Khorana, H.G., 2004. Structural origins of constitutive activation in rhodopsin: Role of the K296/E113 salt bridge. Proceedings of the National Academy of Sciences, 101, pp.12508‑12513. DOI: https://doi.org/10.1073/pnas.0404519101
Kohl, S., Jägle, H., Wissinger, B., and Zobor, D., 2018. Achromatopsia. In: Adam, M.P., Ardinger, H.H. and Pagon, R.A., Eds. GeneReviews®. University of Washington, Seattle (WA). Available from: https://www.ncbi.nlm.nih.gov/ books/NBK1418 [Last accessed on 2025 Sep 29].
Kuo, H.K., Tsao, S.T., and Pei-Chang, W.U., 2023. Prevalence of congenital color vision deficiency in southern taiwan and detection of female carriers by visual pigment gene analysis. International Journal of Molecular Sciences, 24, p.15247. DOI: https://doi.org/10.3390/ijms242015247
Kurosaki, T., Popp, M.W., and Maquat, L.E., 2019. Quality and quantity control of gene expression by nonsense-mediated mRNA decay. Nature Reviews Molecular Cell biology, 20, pp.406‑420. DOI: https://doi.org/10.1038/s41580-019-0126-2
Lejeune, F., 2017. Nonsense-mediated mRNA decay at the crossroads of many cellular pathways. BMB Reports, 50, p.175. DOI: https://doi.org/10.5483/BMBRep.2017.50.4.015
Lilja, O., 2024. Genetic Variations in Human Opsin Genes. Tampere University, Finland. Migeon, B.R., 2020. X-linked diseases: Susceptible females. Genetics in Medicine, 22, pp.1156-1174. DOI: https://doi.org/10.1038/s41436-020-0779-4
Nathans, J., 1999. The evolution and physiology of human color vision: Insights from molecular genetic studies of visual pigments. Neuron, 24, pp.299-312. DOI: https://doi.org/10.1016/S0896-6273(00)80845-4
Nathans, J., Thomas, D., and Hogness, D.S., 1986. Molecular genetics of human color vision: The genes encoding blue, green, and red pigments. Science, 232, pp.193-202. DOI: https://doi.org/10.1126/science.2937147
Neitz, J., and Neitz, M., 2011. The genetics of normal and defective color vision. Vision Research, 51, pp.633‑651. DOI: https://doi.org/10.1016/j.visres.2010.12.002
Neitz, M., and Neitz, J., 2021. Intermixing the OPN1LW and OPN1MW genes disrupts the exonic splicing code causing an array of vision disorders. Genes, 12, p.1180. DOI: https://doi.org/10.3390/genes12081180
Neitz, M., Neitz, J., and Grishok, A., 1995. Polymorphism in the number of genes encoding long-wavelength-sensitive cone pigments among males with normal color vision. Vision Research, 35, pp.2395-2407. DOI: https://doi.org/10.1016/0042-6989(95)00008-9
Neitz, M., Patterson, S.S., and Neitz, J., 2019. Photopigment genes, cones, and color update: Disrupting the splicing code causes a diverse array of vision disorders. Current Opinion in Behavioral Sciences, 30, pp.60‑66. DOI: https://doi.org/10.1016/j.cobeha.2019.05.004
Neitz, M., Wagner-Schuman, M., Rowlan, J.S., Kuchenbecker, J.A., and Neitz, J., 2022. Insight from OPN1LW gene haplotypes into the cause and prevention of myopia. Genes, 13, p.942. DOI: https://doi.org/10.3390/genes13060942
Ng, P.C., and Henikoff, S., 2003. SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Research, 31, pp.3812‑3814. DOI: https://doi.org/10.1093/nar/gkg509
Orosz, O., Rajta, I., Vajas, A., Takács, L., Csutak, A., Fodor, M., Kolozsvári, B., Resch, M., Sényi, K., and Lesch, B., 2017. Myopia and late-onset progressive cone dystrophy associate to LVAVA/MVAVA exon 3 interchange haplotypes of opsin genes on chromosome X. Investigative Ophthalmology and Visual Science, 58, pp.1834‑1842. DOI: https://doi.org/10.1167/iovs.16-21405
Robinson, P.R., Cohen, G.B., Zhukovsky, E.A., and Oprian, D.D., 1992. Constitutively active mutants of rhodopsin. Neuron, 9, pp.719-725. DOI: https://doi.org/10.1016/0896-6273(92)90034-B
Segre, L., 2019. Eye Anatomy: A Closer Look at the Parts of the Eye. Verywell Health. Available from: https://www.allaboutvision.com/eye-care/eye-anatomy/ overview-of-anatomy [Last accessed on 2025 Sep 29]. Simunovic, M., 2010. Colour vision deficiency. Eye, 24, pp.747-755. DOI: https://doi.org/10.1038/eye.2009.251
Swathi, B., Koushalya, R., Roshan, J.V., and Gowtham, M., 2020. Color blindness algorithm comparison for developing an android application. International Research Journal of Engineering and Technology (IRJET), 7, p. 3608.
Tyagi, S., Nema, P., Tyagi, M., and Agrawal, M., 2024. Association between color vision deficiency and ABO blood group in young adults: A prevalence study. European Journal of Cardiovascular Medicine, 14, pp.173-176.
Vaser, R., Adusumalli, S., Leng, S.N., Sikic, M., and Ng, P.C., 2016. SIFT missense predictions for genomes. Nature protocols, 11, pp.1-9. DOI: https://doi.org/10.1038/nprot.2015.123
Wissinger, B., Baumann, B., Buena-Atienza, E., Ravesh, Z., Cideciyan, A.V., Stingl, K., Audo, I., Meunier, I., Bocquet, B., and Traboulsi, E.I., 2022. The landscape of submicroscopic structural variants at the OPN1LW/OPN1MW gene cluster on Xq28 underlying blue cone monochromacy. Proceedings of the National Academy of Sciences, 119, p.e2115538119. DOI: https://doi.org/10.1073/pnas.2115538119
Yousif, N., Abdullah, M., Abdularazaq, F., Sabir, A., Mohammed, M., and Saleem, N., 2024. Determination of Colorblindness Among Public Secondary School Children in Erbil City. In: 5th International Conference on Biomedical and Health Sciences. Cihan University-Erbil, pp.104-108. DOI: https://doi.org/10.24086/biohs2024/paper.1071
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