Molecular genetic aspects of keratoconus pathogenesis

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Keratoconus is a bilateral, progressive corneal disease affecting all ethnic groups around the world. It is one of the major ocular problems with significant social impacts as the disease affects young generation, and is the leading cause of corneal transplantation. Although keratoconus is associated with genetic and environmental factors, its precise etiology is not yet established. Results from complex segregation analysis and patterns of gene expression show that genetic abnormalities may play an essential role in the susceptibility to keratoconus. There is a strong association between the polymorphism of a number of genes and corneal curvature. These polymorphisms explain only a small percentage of keratoconus cases, so genetic influences on keratoconus are most likely complex and varied. The aim of this review is to briefly provide the current knowledge on the genetic keratoconus basis - to understand the disease pathogenesis.

Alexey N Kulikov

Author for correspondence.
S.M. Kirov Military Medical Academy
Russian Federation, Saint Petersburg, Russia

MD, PhD, DMedSc, professor, head of the department. Ophthalmology Department

Sergey V Churashov
S.M. Kirov Military Medical Academy
Russian Federation, Saint Petersburg, Russia

MD, PhD, DMedSc, assistant professor, professor. Ophthalmology Department

Tatiana A Kamilova
S.M. Kirov Military Medical Academy
Russian Federation, Saint Petersburg, Russia

PhD, Biology, senior research associate. Scientific research laboratory (tissue engineering) of the Scientific research department (of the medical biological research) of the Scientific research center

Vladimir A Reituzov
S.M. Kirov Military Medical Academy
Russian Federation, Saint Petersburg, Russia

MD, PhD, assistant professor. Ophthalmology Department

  • Abu-Amero KK, Al-Muammar AM, Kondkar AA. Genetics of keratoconus: where do we stand? J. Ophthalmol. [Электронный ресурс] 2014. doi: 10.1155/2014/641708.
  • Abu-Amero KK, Kondkar AA, Azad TA, et al. Keratoconus is associated with increased copy number of mitochondrial DNA Mol Vis. 2014;(20):1203-1208. doi: 10.1155/2014/641708.
  • Atilano S.R, Coskun P, Chwa M, et al. Accumulation of mitochondrial DNA damage in keratoconus corneas. Invest Ophthalmol Vis Sci. 2005;46(4):1256-1263. doi: 10.1167/iovs.04-1395.
  • Bae HA, Mills RA, Lindsay RG, et al. Replication and meta-analysis of candidate loci identified variation at RAB3GAP1 associated with keratoconus. Invest Ophthalmol Vis Sci. 2013;54(7):5132-5. doi: 10.1167/iovs.13-12377.
  • Burdon KP, Macgregor S, Bykhovskaya Y, et al. Association of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus. Invest Ophthalmol Vis Sci. 2011;52(11):8514-9. doi: 10.1167/iovs.11-8261.
  • Burdon KP, Vincent AL. Insights into keratoconus from a genetic perspective. Clin Exp Optom. 2013;96(2):146-154. doi: 10.1111/cxo.12024.
  • Bykhovskaya Y, Li X, Epifantseva I, et al. Variation in the lysyl oxidase (LOX) gene is associated with keratoconus in family-based and case-control studies. Invest Ophthalmol Vis Sci. 2012;53(7):4152-4157. doi: 10.1167/iovs.11-9268.
  • Chai D, Gaster RN, Roizenblatt R, et al. Quantitative assessment of UVA-riboflavin corneal cross-linking using nonlinear optical microscopy. Invest Ophthalmol Vis Sci. 2011;52(7):4231-4238. doi: 10.1167/iovs.10-7105.
  • Chang H-Y, Chodosh J. The genetics of keratoconus. Semin Ophthalmol. 2013;28(5-6):275-280. doi: 10.3109/ 08820538.2013.825295.
  • Chwa M, Atilano SR, Hertzog D, et al. Hypersensitive response to oxidative stress in keratoconus corneal fibroblasts. Invest Ophthalmol Vis Sci. 2008;49(10):4361-4369. doi: 10.1167/iovs.08-1969.
  • Ghosh A, Zhou L, Ghosh A, et al. Proteomic and gene expression patterns of keratoconus. Indian J Ophthalmol. 2013;61(8):389-91. doi: 10.4103/0301-4738.116056.
  • Hasanian-Langroudi F, Saravani R, Validad MH, et al. Association of lysyl oxidase (LOX) polymorphisms with the risk of keratoconus in an Iranian population. Ophthalmic Genet. [Электронный ресурс] 2014. doi: 10.3109/13816810.2014.881507.
  • Jeyabalan N, Shetty R, Ghosh A, et al. Genetic and genomic perspective to understand the molecular pathogenesis of keratoconus. Indian J Ophthalmol. 2013;61(8):384-388. doi: 10.4103/0301-4738.116055.
  • Karolak JA, Polakowski P, Szaflik J, et al. Molecular screening of keratoconus susceptibility sequence variants in VSX1, TGFBI, DOCK9, STK24, and IPO5 genes in Polish patients and novel TGFBI variant identification. Ophthalmic Genetics [Электронный ресурс] 2014. doi: 10.3109/13816810.2014.926375.
  • Lechner J, Bae HA, Guduric-Fuchs J, et al. Mutational analysis of MIR184 in sporadic keratoconus and myopia. Invest Ophthalmol Vis Sci. 2013;54(8):5266-5272. doi: 10.1167/iovs.13-12035.
  • Lechner J, Dash DP, Muszynska D, et al. Mutational spectrum of the ZEB1 gene in corneal dystrophies supports a genotype-phenotype correlation. Invest Ophthalmol Vis Sci. 2013;54(5):3215-23. doi: 10.1167/iovs.13-11781.
  • Li X, Bykhovskaya Y, Canedo AL, et al. Genetic association of COL5A1 variants in keratoconus patients suggests a complex connection between corneal thinning and keratoconus. Invest Ophthalmol Vis Sci. 2013;54(4):2696-2704. doi: 10.1167/iovs.13-11601.
  • Li X, Bykhovskaya Y, Tang YG, et al. An association between the calpastatin (CAST) gene and keratoconus. Cornea. 2013;32(5):696-701. doi: 10.1097/ICO.0b013e3182821c1c.
  • Lu Y, Vitart V, Burdon KP, et al. Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus. Nat Genet. 2013;45(2):155-163. doi: 10.1038/ng.2506.
  • Mace M, Galiacy SD, Erraud A, et al. Comparative transcriptome and network biology analyses demonstrate antiproliferative and hyperapoptotic phenotypes in human keratoconus corneas. Invest Ophthalmol Vis Sci. 2011;52(9):6181-6191. doi: 10.1167/iovs.10-70981.
  • Mazzotta C, Traversi C, Raiskup F, et al. First identification of a triple corneal dystrophy association: keratoconus, epithelial basement membrane corneal dystrophy and Fuchs’ endothelial corneal dystrophy. Case Rep Ophthalmol. 2014;5(3):281-8. doi: 10.1159/000367937.
  • Mikami T, Meguro A, Teshigawara T, et al. Interleukin 1 beta promoter polymorphism is associated with keratoconus in a Japanese population. Mol Vis. 2013;(9):845-851.
  • Mootha VV, Kanoff JM, Shankardas J, Dimitrijevich S. Marked reduction of alcohol dehydrogenase in keratoconus corneal fibroblasts. Mol Vis. 2009;(15):706-712.
  • Nielsen K, Birkenkamp-Demtroder K, Ehlers N, Orntoft TF. Identification of differentially expressed genes in keratoconus epithelium analyzed on microarrays. Invest Ophthalmol Vis Sci. 2003;44(6):2466-2476. doi: 10.1167/iovs.02-0671.
  • Nowak DM, Karolak JA, Kubiak J, et al. Substitution at IL1RN and deletion at SLC4A11 segregating with phenotype in familial keratoconus. Invest Ophthalmol Vis Sci. 2013;54(3):2207-15. doi: 10.1167/iovs.13-11592.
  • Rohrbach M, Spencer HL, Porter LF, et al. ZNF469 frequently mutated in the brittle cornea syndrome (BCS) is a single exon gene possibly regulating the expression of several extracellular matrix components. Mol Genet Metab. 2013;109(3):289-295. doi: 10.1016/j.ymgme.2013.04.014.
  • Saee-Rad S, 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;(19):2501-2507.
  • Sahebjada S, Schache M, Richardson AJ, et al. Association of the hepatocyte growth factor gene with keratoconus in an Australian population. PLoS One. 2014;9(1):e84067. doi: 10.1371/journal.pone.0084067.
  • Sahebjada S, Schache M, Richardson AJ, et al. Evaluating the association between keratoconus and the corneal thickness genes in an independent Australian population. Invest Ophthalmol Vis Sci. 2013;54(13):8224-8228. doi: 10.1167/iovs.13-12982.
  • Stabuc-Silih M, Ravnik-Glavac M, Glavac D, et al. Polymorphisms in COL4A3 and COL4A4 genes associated with keratoconus. Mol Vis. 2009;(15):2848-2860.
  • Synowiec E, Wojcik KA, Izdebska J, et al. Polymorphisms of the homologous recombination gene RAD51 in keratoconus and Fuchs endothelial corneal dystrophy. Dis Markers. 2013;35(5):353-362. doi: 10.1155/2013/851817.
  • Vithana ENMP, Ramprasad V, Tan DT, et al. SLC4A11 mutations in Fuchs endothelial corneal dystrophy. Hum Mol Genet. 2008;17(5):656-666. doi: 10.1093/hmg/ddm337.
  • Wheeler J, Hauser MA, Afshari NA, Allingham RR, Liu Y. The genetics of keratoconus: a review. Reprod Syst Sex Disord. 2012;(Suppl.6):pii:001.
  • Wójcik KA, Synowiec E, Jiménez-García M.P. Polymorphism of the transferrin gene in eye diseases: keratoconus and Fuchs endothelial corneal dystrophy. Biomed Res Int. [Электронный ресурс] 2013. doi: 10.1155/2013/247438.
  • Wójcik KA, Synowiec E, Polakowski P, et al. Polymorphism of the flap endonuclease 1 gene in keratoconus and Fuchs endothelial corneal dystrophy. Int J Mol Sci. 2014;15(8):14786-14802. doi: 10.3390/ijms150814786.
  • Wojcik KA, Synowiec E, Sobierajczyk K, et al. Polymorphism of the DNA base excision repair genes in keratoconus. Int J Mol Sci. 2014;15(11):19682-19699. doi: 10.3390/ijms151119682.


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