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Genetic aspects of keratoconus development

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Abstract

Keratoconus (KC) is the most common form of keratoectasia characterized by changes in corneal topography and its thinning, stretching, and protrusion. The hereditary or genetic theory of keratoconus development is widely recognized. To date, a large number of candidate genes have been investigated in patients with KC. One of the most important of them are the gene encoding a homeodomain-containing protein that belongs to the subfamily of paired-like homeodomain proteins (VSX1), superoxidedismutase 1 (SOD1) gene, and the gene of lysyloxidase (LOX). The linkage analysis reveals over 17 chromosomal regions mutations in which can lead to the development of KC. In families with a hereditary form of keratoconus by GWAS analysis, the association of central corneal thickness (CCT) with a number of genetic loci is revealed. Thus, diverse results of genetic studies and a large number of identified chromosomal regions associated with keratoconus, firstly, show marked genetic heterogeneity of the disease and, secondly, are associated with challenges in DNA diagnosis of this disease. However, there are prerequisites that keratoconus belongs to both hereditary and genetically caused diseases and identified genetic variants are specific both to individual populations and to certain ethnic groups in general.

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References

  1. Sugar, J. and Macsai, M.S., What causes keratoconus? Cornea, 2012, vol. 31, no. 6, pp. 716–719. doi 10.1097/ICO.0b013e31823f8c72

  2. Edwards, M, The genetics of keratoconus, Clin. Exp. Ophthalmol., 2001, vol. 29, no. 6, pp. 345–351.

    Article  CAS  PubMed  Google Scholar 

  3. Bikbov, M.M. and Bikbova, G.M., Ektazii rogovitsy (patogenez, patomorfologiya, klinika, diagnostika, lechenie) (Corneal Ectasia (Pathogenesis, Pathomorphology, Clinical Picture, Diagnosis, Treatment)), Moscow: Oftal’mologiya, 2011.

    Google Scholar 

  4. Oganisyan, K.Kh., Genetic aspects of keratoconus (review), Sbornik nauchnykh trudov Mezhdunarodnoi nauchno-prakticheskoi konferentzii po oftal’mokhirurgii “Vostok-Zapad” (Proceedings of International Scientific and Practical Conference for Ophthalmic Surgery “East–West”), Ufa, 2013, p. 98.

    Google Scholar 

  5. Bikbov, M.M., Surkova, V.K., and Oganisyan, K.Kh., Keratoconus as a manifestation of connective tissue dysplasia, Oftal’mologiya, 2015, vol. 12, no. 1, pp. 4–7.

    Google Scholar 

  6. Mglinets, V.A, Molecular genetics of development of cornea, Russ. J. Genet., 2015, vol. 51, no. 1, pp. 1–8.

    Article  CAS  Google Scholar 

  7. Surkova, V.K. and Oganisyan, K.Kh., Epidemiology of primary corneal ectasia, Vestn. Orenburg. Gos. Univ., 2015, vol. 187, no. 12, pp. 234–238.

    Google Scholar 

  8. Davidson, A.E., Hayes, S., Hardcastle, A.J., et al., The pathogenesis of keratoconus, Eye, 2014, vol. 28, no. 2, pp. 189–195. doi 10.1038/eye.2013.278

    Article  CAS  PubMed  Google Scholar 

  9. Abu-Amero, K.K., Al-Muammar, A.M., and Kondkar, A.A, Genetics of keratoconus: where do we stand?, J. Ophthalmol., 2014, vol. 2014. doi 10.1155/2014/641708.641708

    Google Scholar 

  10. Wang, Y., Rabinowitz, Y.S., Rotter, J.I., et al., Genetic epidemiological study of keratoconus: evidence for major gene determination, Am. J. Med. Genet., 2000, vol. 93, no. 5, pp. 403–409.

    Article  CAS  PubMed  Google Scholar 

  11. Avetisov, S.E., Novikov, I.A., and Pateyuk, A.S, Keratoconus: ethiological factors and associated symptoms, Vestn. Oftal’mol., 2014, no. 4, pp. 110–113.

    Google Scholar 

  12. Waked, N., Fayad, A.M., Fadlallah, A., et al., Keratoconus screening in a Lebanese students’ population, J. Fr. Ophtalmol., 2012, vol. 35, no. 1, pp. 23–29.

    Article  CAS  PubMed  Google Scholar 

  13. Hashemi, H., Beiranvand, A., and Khabazkhoob, M, Prevalence of keratoconus in a population-based study in Shahroud, Cornea, 2013, vol. 32, no. 11, pp. 1441–1445.

    Article  PubMed  Google Scholar 

  14. Zadnik, K., Barr, J.T., and Edrington, T.B, Baseline findings in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) study, Invest. Ophthalmol. Vis. Sci., 1998, vol. 39, no. 13, pp. 2537–2546.

    CAS  PubMed  Google Scholar 

  15. Assiri, A.A., Yousuf, B.I., Quantock, A.J., et al., Incidence and severity of keratoconus in Asir province, Saudi Arabia, Br. J. Ophthalmol., 2005, vol. 89, no. 11, pp. 1403–1406.

    Article  CAS  PubMed  Google Scholar 

  16. Millodot, M., Shneor, E., Albou, S., et al., Prevalence and associated factors of keratoconus in Jerusalem: a cross-sectional study, Ophthalmic Epidemiol., 2011, vol. 18, no. 2, pp. 91–97.

    Article  PubMed  Google Scholar 

  17. Owens, H. and Gamble, G., A profile of keratoconus in New Zealand, Cornea, 2003, vol. 22, no. 2, pp. 122–125.

    Article  PubMed  Google Scholar 

  18. Hosseini, S.M., Herd, S., Vincent, A.L., et al., Genetic analysis of chromosome 20-related posterior polymorphous corneal dystrophy: genetic heterogeneity and exclusion of three candidate genes, Mol. Vis., 2008, vol. 14, pp. 71–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Semina, E.V. Mintz-Hittner, H.A., et al., Isolation and characterization of a novel human paired-like homeodomain-containing transcription factor gene, VSX1, expressed in ocular tissues, Genomics, 2000, vol. 63, no. 2, pp. 289–293. doi 10.1006/geno. 1999.6093

    CAS  PubMed  Google Scholar 

  20. Hayashi, T., Huang, J., and Deeb, S.S., RINX(VSX1), a novel homeobox gene expressed in the inner nuclear layer of the adult retina, Genomics, 2000, vol. 67, no. 2, pp. 128–139. doi 10.1006/geno.2000.6248

    Article  CAS  PubMed  Google Scholar 

  21. Héon, E., Greenberg, A., Kopp, K.Kl., et al., VSX1: a gene for posterior polymorphous dystrophy and keratoconus, Hum. Mol. Genet., 2002, vol. 11, no. 9, pp. 1029–1036. doi 10.1093/hmg/11.9.1029

    Article  PubMed  Google Scholar 

  22. Ohtoshi, A., Wang, S.W., and Maeda, H, Regulation of retinal cone bipolar cell differentiation and photopic vision by the CVC homeobox gene Vsx1, Curr. Biol., 2004, vol. 14, no. 6, pp. 530–536. doi 10.1016/j.cub. 2004.02.027

    Article  CAS  PubMed  Google Scholar 

  23. Watson, T. and Chow, R.L, Absence of Vsx1 expression in the normal and damaged mouse cornea, Mol. Vis., 2011, vol. 17, pp. 737–744.

    PubMed  PubMed Central  Google Scholar 

  24. Bisceglia, L., Ciaschetti, M., De Bonis, P., et al., VSX1 mutational analysis in a series of Italian patients affected by keratoconus: detection of a novel mutation, Invest. Ophthalmol. Vis. Sci., 2005, vol. 46, pp. 39–45. doi 10.1167/iovs.04-0533

    Article  PubMed  Google Scholar 

  25. Dash, D.P., George, S., O’Prey, D., et al., Mutational screening of VSX1 in keratoconus patients from the European population, Eye, 2010, vol. 24, pp. 1085–1092.

    Article  CAS  PubMed  Google Scholar 

  26. Tang, Y.G., Rabinowitz, Y.S., and Taylor, K.D, Genomewide linkage scan in a multigeneration Caucasian pedigree identifies a novel locus for keratoconus on chromosome 5q14.3-q21.1, Genet. Med., 2005, vol. 7, no. 6, pp. 397–405. doi 10.1097/01.gim. 0000170772.41860.54

    Article  CAS  PubMed  Google Scholar 

  27. Romero-Jiménez, M., Santodomingo-Rubido, J., and Wolffsohn, J.S, Keratoconus: a review, Contact Lens Anterior Eye, 2010, vol. 33, no. 4, pp. 157–166. doi 10.1016/j.clae.2010.04.006

    Article  PubMed  Google Scholar 

  28. Stabuc-Silih, M., Strazisar, M., Ravnik-Glavac, M., et al., Genetics and clinical characteristics of keratoconus, Acta Dermatovenerol. Alp., Pannonica, Adriat., 2010, vol. 19, no. 2, pp. 3–10.

    Google Scholar 

  29. Gondhowiardjo, T.D. and van Haeringen, N.J, Corneal aldehyde dehydrogenase, glutathione reductase, and glutathione S-transferase in pathologic corneas, Cornea, 1993, vol. 12, pp. 310–314.

    CAS  PubMed  Google Scholar 

  30. Kenney, M.C., Chwa, M., and Atilano, S.R, Increased levels of catalase and cathepsin V/L2 but decreased TIMP-1 in keratoconus corneas: evidence that oxidative stress plays a role in this disorder, Invest. Ophthalmol. Vis. Sci., 2005, vol. 46, pp. 823–832.

    Article  PubMed  Google Scholar 

  31. Behndig, A., Karlsson, K., Johansson, B.O., et al., Superoxide dismutase isoenzymes in the normal and diseased human cornea, Invest. Ophthalmol. Vis. Sci., 2001, vol. 42, pp. 2293–2296.

    CAS  PubMed  Google Scholar 

  32. Buddi, R., Lin, B., Atilano, S.R., Zorapapel, N.C., et al., Evidence of oxidative stress in human corneal diseases, J. Histochem. Cytochem., 2002, vol. 50, pp. 341–351.

    Article  CAS  PubMed  Google Scholar 

  33. Chwa, M., Atilano, S.R., Reddy, V., et al., Increased stress-induced generation of reactive oxygen species and apoptosis in human keratoconus fibroblasts, Invest. Ophthalmol. Vis. Sci., 2006, vol. 47, pp. 1902–1910.

    Article  PubMed  Google Scholar 

  34. Chwa, M., Atilano, S.R., and Hertzog, D, Hypersensitive response to oxidative stress in keratoconus corneal fibroblasts, Invest. Ophthalmol. Vis. Sci., 2008, vol. 49, pp. 4361–4369.

    Article  PubMed  Google Scholar 

  35. Shoham, A., Hadziahmetovic, M., Dunaief, J.L., et al., Oxidative stress in diseases of the human cornea, Free Radic. Biol. Med., 2008, vol. 45, pp. 1047–1055.

    Article  CAS  PubMed  Google Scholar 

  36. Noor, R., Mittal, S., and Iqbal, J, Superoxide dismutase–applications and relevance to human diseases, Med. Sci. Monitor., 2002, vol. 8, no. 9, pp. 210–215.

    Google Scholar 

  37. Lewis, P. and Rowland Neil, A., Amyotrophic lateral sclerosis, N. Engl. J. Med., 2001, vol. 344, no. 22, pp. 1688–1700.

    Article  Google Scholar 

  38. Majoor-Krakauer, D. and Willems, P.J, Genetic epidemiology of amyotrophic lateral sclerosis, Clin. Genet., 2003, vol. 63, no. 2, pp. 83–101.

    Article  CAS  PubMed  Google Scholar 

  39. Ticozzi, N., Tiloca, C., Morelli, C., et al., Genetics of familial amyotrophic lateral sclerosis, Arch. Ital. Biol., 2011, vol. 149, pp. 65–82.

    PubMed  Google Scholar 

  40. Stoiber, J., Muss, W., and Ruckhofer, J, Acute keratoconus with perforation in a patient with Down’s syndrome, Br. J. Ophthalmol., 2003, vol. 87, p. 120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Soriano, L., Munoz Calvo, M., and Pozo Roman, J, Graves disease in patients with Down’s syndrome, An. Pediatr., 2003, vol. 58, pp. 63–66.

    Article  Google Scholar 

  42. Rabinowitz, Y.S, Keratoconus, Surv. Ophthalmol., 1998, vol. 42, pp. 297–319.

    Article  CAS  PubMed  Google Scholar 

  43. Štabuc-Šilih, M., Stražišar, M., Hawlina, M., et al., Absence of pathogenic mutations in VSX1 and SOD1 genes in patients with keratoconus, Cornea, 2010, vol. 29, no. 2, pp. 172–176. doi 10.1097/ICO. 0b013e3181aebf7a

    Article  PubMed  Google Scholar 

  44. Bonis, P., Laborante, A., and Pizzicoli, C, Mutational screening of VSX1, SPARC, SOD1, LOX, and TIMP3 in keratoconus, Mol. Vision, 2011, vol. 17, pp. 2482–2494.

    Google Scholar 

  45. Sussan, T.E., Yang, A., Li, F., et al., Trisomy represses ApcMin-mediated tumours in mouse models of Down’s syndrome, Nature, 2008, vol. 451, pp. 73–75. doi 10.1038/nature06446

    Article  CAS  PubMed  Google Scholar 

  46. Udar, N., Atilano, S.R., and Brown, D.J., SOD1: a candidate gene for keratoconus, Invest. Ophthalmol. Vis. Sci., 2006, vol. 47, no. 8, pp. 3345–3351. doi 10.1167/iovs.05-1500

    Article  PubMed  Google Scholar 

  47. Udar, N., Atilano, S.R., Small, K., et al., SOD1 haplotypes in familial keratoconus, Cornea, 2009, vol. 28, no. 8, pp. 902–907. doi 10.1097/ICO. 0b013e3181983a0c

    Article  PubMed  Google Scholar 

  48. Saee-Rad, S.1., Hashemi, H., Miraftab, M., et al., Mutation analysis of VSX1 and SOD1 in Iranian patients with keratoconus, Mol. Vis., 2011, vol. 17, pp. 3128–3136.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Saee-Rad, S.1., Raoofian, R., Mahbod, M., et al., Analysis of superoxide dismutase 1, dual-specificity phosphatase 1, and transforming growth factor, beta 1 genes expression in keratoconic and non-keratoconic corneas, Mol. Vis., 2013, vol. 19, pp. 2501–2507.

    CAS  Google Scholar 

  50. Moschos, M., Kokolakis, N., Gazouli, M., et al., Polymorphism analysis of VSX1 and SOD1 genes in Greek patients with keratoconus, Ophthalmic Genet., 2015, vol. 36, no. 3, pp. 213–217. doi 10.3109/13816810.2013.843712

    Article  PubMed  Google Scholar 

  51. Al-Muammar, A.M., Kalantan, H., and Azad, T.A, Analysis of the SOD1 gene in keratoconus patients from Saudi Arabia, Ophthalmic Genet., 2015, vol. 36, no. 4, pp. 373–375. doi 10.3109/13816810.2014.889173

    Article  CAS  PubMed  Google Scholar 

  52. Kok, Y.O., Ling, G.F., and Loon, S.C, Review: keratoconus in Asia, Cornea, 2012, vol. 31, no. 5, pp. 581–593. doi 10.1097/ico.0b013e31820cd61d

    Article  PubMed  Google Scholar 

  53. Hamalainen, E.R., Jones, T.A., Sheer, D., et al., Molecular cloning of human lysyl oxidase and assignment of the gene to chromosome 5q23.3-31.2, Genomics, 1991, vol. 11, pp. 508–516.

    Article  CAS  PubMed  Google Scholar 

  54. Mäki, J.M, Lysyl oxidases in mammalian development and certain pathological conditions, Histol. Histopathol., 2009, vol. 24, pp. 651–660.

    PubMed  Google Scholar 

  55. Cano, A., Santamaria, P.G., and Moreno-Bueno, G., LOXL2 in epithelial cell plasticity and tumor progression, Future Oncol., 2012, vol. 8, pp. 1095–1080.

    Article  CAS  PubMed  Google Scholar 

  56. Coral, K., Angayarkanni, N., Madhavan, J., et al., Lysyl oxidase activity in the ocular tissues and the role of LOX in proliferative diabetic retinopathy and rhegmatogenous retinal detachment, Invest. Ophthalmol. Vis. Sci., 2008, vol. 49, pp. 4746–4752.

    Article  PubMed  Google Scholar 

  57. Lucero, H.A1. and Kagan, H.M, Lysyl oxidase: an oxidative enzyme and effector of cell function, Cell Mol. Life Sci., 2006, vol. 63, pp. 2304–2316.

    Article  CAS  PubMed  Google Scholar 

  58. Nielsen, K., Birkenkamp-Demtroder, K., Ehlers, N., et al., Identification of differentially expressed genes in keratoconus epithelium analyzed on microarrays, Invest. Ophthalmol. Vis. Sci., 2003, vol. 44, pp. 2466–2476.

    Article  PubMed  Google Scholar 

  59. Dudakova, L., Liskova, P., Trojek, T., et al., Changes in lysyl oxidase (LOX) distribution and its decreased activity in keratoconus corneas, Exp. Eye Res., 2012, vol. 104, pp. 74–81.

    Article  CAS  PubMed  Google Scholar 

  60. Shetty, R., Sathyanarayanamoorthy, A., Ramachandra, R.A., et al., Attenuation of lysyl oxidase and collagen gene expression in keratoconus patient corneal epithelium corresponds to disease severity, Mol. Vis., 2015, vol. 21, pp. 12–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Bisceglia, L., de Bonis, P., and Pizzicoli, C, Linkage analysis in keratoconus: replication of locus 5q21.2 and identification of other suggestive loci, Invest. Ophthalmol. Vis. Sci., 2009, vol. 50, no. 3, pp. 1081–1086. doi 10.1167/iovs.08-2382

    Article  PubMed  Google Scholar 

  62. Dudakova, L., Palos, M., Jirsova, K., et al., Validation of rs2956540:G>C and rs3735520:G>A association with keratoconus in a population of European descent, Eur. J. Hum. Genet., 2015, vol. 23, no. 11, pp. 1581–1583. doi 10.1038/ejhg.2015.28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wheeler, J., Hauser, M.A., Afshari, N.A., et al., The genetics of keratoconus: a review, Reprod. Syst. Sex. Disord., 2012, suppl. 6, p. 001. doi 10.4172/2161-038X.S6-001

    Google Scholar 

  64. Burdon, K.P., Coster, D.J., Charlesworth, J.C., et al., Apparent autosomal dominant keratoconus in a large Australian pedigree accounted for by digenic inheritance of two novel loci, Hum. Genet., 2008, vol. 124, no. 4, pp. 379–386. doi 10.1007/s00439-008-0555-z

    Article  PubMed  Google Scholar 

  65. Hutchings, H., Ginisty, H., and Gallo, M, Identification of a new locus for isolated familial keratoconus at 2p24, J. Med. Genet., 2005, vol. 42, no. 1, pp. 88–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Brancati, F., Valente, E.M., and Sarkozy, A., A locus for autosomal dominant keratoconus maps to human chromosome 3p14-q13, J. Med. Genet., 2004, vol. 41, pp. 188–192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Li, X., Rabinowitz, Y.S., and Tang, Y.G., Two-stage genome-wide linkage scan in keratoconus sib pair families, Invest. Ophthalmol. Vis. Sci., 2006, vol. 47, no. 9, pp. 3791–3795. doi 10.1167/iovs.06-0214

    Article  PubMed  Google Scholar 

  68. Gajecka, M., Radhakrishna, U., Winters, D., et al., Localization of a gene for keratoconus to a 5.6-Mb interval on 13q32, Invest. Ophthalmol. Vis. Sci., 2009, vol. 50, no. 4, pp. 1531–1539. doi 10.1167/iovs.08- 2173

    Article  PubMed  Google Scholar 

  69. Liskova, P., Hysi, P.G., Waseem, N., et al., Evidence for keratoconus susceptibility locus on chromosome 14: a genome-wide linkage screen using single-nucleotide polymorphism markers, Arch. Ophthalmol., 2010, vol. 128, pp. 1191–1195.

    Article  CAS  PubMed  Google Scholar 

  70. Hughes, A.E., Dash, D.P., Jackson, A.J., et al., Familial keratoconus with cataract: linkage to the long arm of chromosome 15 and exclusion of candidate genes, Invest. Ophthalmol. Vis. Sci., 2003, vol. 44, no. 12, pp. 5063–5066. doi 10.1167/iovs.03-0399

    Article  PubMed  Google Scholar 

  71. Tyynismaa, H., Sistonen, P., Tuupanen, S., et al., A locus for autosomal dominant keratoconus: linkage to 16q22.3-q23.1 in Finnish families, Invest. Ophthalmol. Vis. Sci., 2002, vol. 43, no. 10, pp. 3160–3164.

    PubMed  Google Scholar 

  72. Hameed, A., Khaliq, S., Ismail, M., et al., A novel locus for Leber congenital amaurosis (LCA4) with anterior keratoconus mapping to chromosome 17p13, Invest. Ophthalmol. Vis. Sci., 2000, vol. 41, pp. 629–633.

    CAS  PubMed  Google Scholar 

  73. Fullerton, J., Paprocki, P., Foote, S., et al., Identityby-descent approach to gene localisation in eight individuals affected by keratoconus from north-west Tasmania, Australia, Hum. Genet., 2002, vol. 110, pp. 462–470.

    Article  CAS  Google Scholar 

  74. Bykhovskaya, Y., Li, X., Taylor, K.D., et al., Linkage analysis of high-density SNPs confirms keratoconus locus at 5q chromosomal region, Ophthalmic Genet., 2014. doi 10.3109/13816810.2014.889172

    Google Scholar 

  75. Czugala, M., Karolak, J.A., Nowak, D.M., et al., Novel mutation and three other sequence variants segregating with phenotype at keratoconus 13q32 susceptibility locus, Eur. J. Hum. Genet., 2012, vol. 20, no. 4, pp. 389–397. doi 10.1038/ejhg.2011.203

    Article  CAS  PubMed  Google Scholar 

  76. Kwofie, M.A. and Skowronski, J, Specific recognition of Rac2 and Cdc42 by DOCK2 and DOCK9 guanine nucleotide exchange factors, J. Biol. Chem., 2008, vol. 283, no. 6, pp. 3088–3096. doi 10.1074/jbc. M705170200

    Article  CAS  PubMed  Google Scholar 

  77. Meola, N., Gennarino, V., and Banfi, S., microRNAs and genetic diseases, PathoGenetics, 2009, vol. 2, no. 1. doi 10.1186/1755-8417-2-7

  78. Ambros, V., Bartel, B., Bartel, D.P., et al., A uniform system for microRNA annotation, RNA, 2003, vol. 9, pp. 277–279.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Jones, P.F., Jakubowicz, T., Pitossi, F.J., et al., Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily, Proc. Natl. Acad. Sci. U.S.A., 1991, vol. 88, pp. 4171–4175. doi 10.1073/pnas.88.10.4171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Hughes, A.E., Bradley, D.T., Campbell, M., et al., Mutation altering the miR-184 seed region causes familial keratoconus with cataract, Am. J. Hum. Genet., 2011, vol. 89, no. 5, pp. 628–633. doi 10.1016/j. ajhg.2011.09.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Lechner, J., Porter, L.F., Rice, A., et al., Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus, Hum. Mol. Genet., 2014, vol. 23, no. 20, pp. 5527–5535. doi 10.1093/hmg/ddu253

    Article  CAS  PubMed  Google Scholar 

  82. Abu-Amero, K.K., Helwa, I., Al-Muammar, A., et al., Screening of the Seed Region of MIR184 in keratoconus patients from Saudi Arabia, Biomed. Res. Int., 2015. doi 10.1155/2015/604508

    Google Scholar 

  83. Lu, Y., Dimasi, D.P., Hysi, P.G., et al., Common genetic variants near the Brittle Cornea Syndrome locus ZNF469 influence the blinding disease risk factor central corneal thickness, PLoS Genet., 2010, vol. 6, no. 5. doi 10.1371/journal.pgen.1000947. e1000947

  84. Vitart, V., Bencic, G., Hayward, C., et al., New loci associated with central cornea thickness include COL5A1, AKAP13 and AVGR8, Hum. Mol. Genet., 2010, vol. 19, no. 21, pp. 4304–4311. doi 10.1093/hmg/ddq349

    Article  CAS  PubMed  Google Scholar 

  85. Vithana, E.N., Aung, T., Khor, C.C., et al., Collagenrelated genes influence the glaucoma risk factor, central corneal thickness, Hum. Mol. Genet., 2011, vol. 20, no. 4, pp. 649–658. doi 10.1093/hmg/ddq511

    Article  CAS  PubMed  Google Scholar 

  86. Lu, Y., Vitart, V., Burdon, K.P., et al., Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus, Nat. Genet., 2013, vol. 45, no. 2, pp. 155–163. doi 10.1038/ng.2506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Gao, X., Gauderman, W.J., Liu, Y., et al., A genomewide association study of central corneal thickness in Latinos, Invest. Ophthalmol. Vis. Sci., 2013, vol. 54, no. 4, pp. 2435–2443. doi 10.1167/iovs.13-11692

    Article  PubMed  PubMed Central  Google Scholar 

  88. Vincent, A.L., Jordan, C.A., Cadzow, M.J., et al., Mutations in the zinc finger protein gene, ZNF469, contribute to the pathogenesis of keratoconus, Invest. Ophthalmol. Vis. Sci., 2014, vol. 55, no. 9, pp. 5629–5635.

    CAS  PubMed  Google Scholar 

  89. Liu, Y., Abu-Amero, K.K., Bykhovskaya, Y., et al., Genomic deletions of RXRA-COL5A1,FAM46AIBTK,HS3ST3B1-PMP22, and GRIA4 in familial keratoconus patients, Proceedings of the ARVO Annual Meeting, Orlando, Fla, 2014.

    Google Scholar 

  90. Li, X., Bykhovskaya, Y., Haritunians, T., et al., A genome-wide association study identifies a potential novel gene locus for keratoconus, one of the commonest causes for corneal transplantation in developed countries, Hum. Mol. Genet., 2012, vol. 21, no. 2, pp. 421–429. doi 10.1093/hmg/ddr460

    PubMed  Google Scholar 

  91. Bae, H.A., Mills, R.D., Lindsay, R.G., et al., Replication and meta-analysis of candidate loci identified variation at RAB3GAP1 associated with keratoconus, Invest. Ophthalmol. Vis. Sci., 2013, vol. 54, no. 7, pp. 5132–5135. doi 10.1167/iovs.13-12377

    Article  PubMed  PubMed Central  Google Scholar 

  92. Aligianis, I.A., Johnson, C.A., Gissen, P., et al., Mutations of the catalytic subunit of RAB3GAP cause Warburg Micro syndrome, Nat. Genet., 2005, vol. 37, no. 3, pp. 221–223. doi 10.1038/ng1517

    Article  CAS  PubMed  Google Scholar 

  93. Handley, M.T., Morris-Rosendahl, D.J., Brown, S., et al., Mutation spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and genotype–phenotype correlations in Warburg Micro syndrome and Martsolf syndrome, Hum. Mutat., 2013, vol. 34, no. 5, pp. 686–696. doi 10.1002/humu.22296

    CAS  PubMed  Google Scholar 

  94. Morris-Rosendahl, D.J., Segel, R., Bor, A.P., et al., New RAB3GAP1 mutations in patients with Warburg Micro syndrome from different ethnic backgrounds and a possible founder effect in the Danish, Eur. J. Human Genet., 2010, vol. 18, no. 10, pp. 1100–1106. doi 10.1038/ejhg.2010.79

    Article  CAS  Google Scholar 

  95. Yüksel, A., Yesil, G., Aras, C., et al., Warburg Micro syndrome in a Turkish boy, Clin. Dysmorphol., 2007, vol. 16, no. 2, pp. 89–93. doi 10.1097/mcd. 0b013e328054c404

    Article  PubMed  Google Scholar 

  96. Burdon, K.P., Macgregor, S., Bykhovskaya, Y., et al., Association of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus, Invest. Ophthalmol. Vis. Sci., 2011, vol. 52, no. 11, pp. 8514–8519. doi 10.1167/iovs.11-8261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Sahebjada, S., Schache, M., and Richardson, A.J, Association of the hepatocyte growth factor gene with keratoconus in an Australian population, PLoS One, 2014, vol. 9, no. 1. doi 10.1371/journal.pone.0084067. e84067

  98. Veerappan, S., Pertile, K.K., Islam, A., et al., Role of the hepatocyte growth factor gene in refractive error, Ophthalmology, 2010, vol. 117, no. 2, pp. 239–245. doi 10.1016/j.ophtha.2009.07.002

    Article  PubMed  Google Scholar 

  99. Yanovitch, T., Li, Y.-J., Metlapally, R., et al., Hepatocyte growth factor and myopia: genetic association analyses in a Caucasian population, Mol. Vis., 2009, vol. 15, pp. 1028–1035.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Abu-Amero, K.K., Hellani, A.M., Al Mansouri, S.M., et al., High-resolution analysis of DNA copy number alterations in patients with isolated sporadic keratoconus, Mol. Vis., 2011, vol. 17, pp. 822–866.

    PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Ufa Eye Research Institute, Academy of Sciences of the Republic of Bashkortostan, Ufa, 450008, Russia

    M. M. Bikbov, E. L. Usubov & K. Kh. Oganisyan

  2. Institute of Biochemistry and Genetics, Ufa Scientific Center, Russian Academy of Sciences, Ufa, 450054, Russia

    S. L. Lobov, L. U. Dzhemileva & E. K. Khusnutdinova

  3. Department of Human Reproductive Health, Bashkir State Medical University, Ufa, 450008, Russia

    L. U. Dzhemileva

  4. Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, 450076, Russia

    R. R. Khasanova & E. K. Khusnutdinova

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  1. M. M. Bikbov
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  2. E. L. Usubov
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  3. K. Kh. Oganisyan
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  4. S. L. Lobov
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  5. R. R. Khasanova
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  6. L. U. Dzhemileva
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  7. E. K. Khusnutdinova
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Correspondence to L. U. Dzhemileva.

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Original Russian Text © M.M. Bikbov, E.L. Usubov, K.Kh. Oganisyan, S.L. Lobov, R.R. Khasanova, L.U. Dzhemileva, E.K. Khusnutdinova, 2017, published in Genetika, 2017, Vol. 53, No. 5, pp. 517–525.

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Bikbov, M.M., Usubov, E.L., Oganisyan, K.K. et al. Genetic aspects of keratoconus development. Russ J Genet 53, 519–527 (2017). https://doi.org/10.1134/S1022795417040020

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