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Genetics of Corneal Disease

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Foundations of Corneal Disease

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Abstract

Genetic mutation can result in insignificant corneal changes that can simply be incidental findings on exam or can result in defects of enormous visual consequence. The more substantial phenotypes tend to be secondary to mutations that cause changes in gene expression early in embryogenesis. Less devastating mutations are those that cause a slow degeneration over time. In this chapter we will explore both ends of the spectrum and will discuss each disease entity in detail including presenting signs and symptoms as well as the genes responsible for each. We will also highlight corneal diseases that express variability in penetrance as well as those that exhibit allelic and locus heterogeneity.

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References

  1. Ma AS, Grigg JR, Jamieson RV. Phenotype-genotype correlations and emerging pathways in ocular anterior segment dysgenesis. Hum Genet. 2018.

    Google Scholar 

  2. Ito YA, Walter MA. Genomics and anterior segment dysgenesis: a review. Clin Exp Ophthalmol. 2014;42:13–24.

    Article  PubMed  Google Scholar 

  3. Rennie CA, Chowdhury S, Khan J, et al. The prevalence and associated features of posterior embryotoxon in the general ophthalmic clinic. Eye (Lond). 2005;19:396–9.

    Article  CAS  Google Scholar 

  4. Berry FB, Lines MA, Oas JM, et al. Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis. Hum Mol Genet. 2006;15:905–19.

    Article  CAS  PubMed  Google Scholar 

  5. Seifi M, Walter MA. Axenfeld-Rieger syndrome. Clin Genet. 2018;93:1123–30.

    Article  CAS  PubMed  Google Scholar 

  6. Moyers RE. Handbook of orthodontics for the student and practitioner. 3rd ed. Chicago: Yearbook; 1973.

    Google Scholar 

  7. Bhandari R, Ferri S, Whittaker B, Liu M, Lazzaro DR. Peters anomaly: review of the literature. Cornea. 2011;30:939–44.

    Article  PubMed  Google Scholar 

  8. Nischal KK, Naor J, Jay V, MacKeen LD, Rootman DS. Clinicopathological correlation of congenital corneal opacification using ultrasound biomicroscopy. Br J Ophthalmol. 2002;86:62–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yang LL, Lambert SR, Lynn MJ, Stulting RD. Surgical management of glaucoma in infants and children with Peters’ anomaly: long-term structural and functional outcome. Ophthalmology. 2004;111:112–7.

    Article  PubMed  Google Scholar 

  10. Vincent A, Billingsley G, Priston M, et al. Further support of the role of CYP1B1 in patients with Peters anomaly. Mol Vis. 2006;12:506–10.

    CAS  PubMed  Google Scholar 

  11. Mackey DA, Buttery RG, Wise GM, Denton MJ. Description of X-linked megalocornea with identification of the gene locus. Arch Ophthalmol. 1991;109:829–33.

    Article  CAS  PubMed  Google Scholar 

  12. Webb TR, Matarin M, Gardner JC, et al. X-linked megalocornea caused by mutations in CHRDL1 identifies an essential role for ventroptin in anterior segment development. Am J Hum Genet. 2012;90:247–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang P, Sun W, Li S, Xiao X, Guo X, Zhang Q. PAX6 mutations identified in 4 of 35 families with microcornea. Invest Ophthalmol Vis Sci. 2012;53:6338–42.

    Article  CAS  PubMed  Google Scholar 

  14. Harissi-Dagher M, Colby K. Anterior segment dysgenesis: Peters anomaly and sclerocornea. Int Ophthalmol Clin. 2008;48:35–42.

    Article  PubMed  Google Scholar 

  15. Elliott JH, Feman SS, O’Day DM, Garber M. Hereditary sclerocornea. Arch Ophthalmol. 1985;103:676–9.

    Article  CAS  PubMed  Google Scholar 

  16. Pantoja-Melendez C, Ali M, Zenteno JC. An epidemiological investigation of a Forkhead box protein E3 founder mutation underlying the high frequency of sclerocornea, aphakia, and microphthalmia in a Mexican village. Mol Vis. 2013;19:1866–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Vanathi M, Panda A, Kai S, Sen S. Corneal keloid. Ocul Surf. 2008;6:186–97.

    Article  CAS  PubMed  Google Scholar 

  18. Song E, Luo N, Alvarado JA, et al. Ocular pathology of oculocerebrorenal syndrome of Lowe: novel mutations and genotype-phenotype analysis. Sci Rep. 2017;7:1442.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Ramappa M, Chaurasia S, Chakrabarti S, Kaur I. Congenital corneal anesthesia. J AAPOS. 2014;18:427–32.

    Article  PubMed  Google Scholar 

  20. Mantelli F, Nardella C, Tiberi E, Sacchetti M, Bruscolini A, Lambiase A. Congenital corneal anesthesia and neurotrophic keratitis: diagnosis and management. Biomed Res Int. 2015;2015:805876.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Weiss JS, Moller HU, Lisch W, et al. The IC3D classification of the corneal dystrophies. Cornea. 2008;27(Suppl 2):S1–83.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Vincent AL. Corneal dystrophies and genetics in the International Committee for Classification of Corneal Dystrophies era: a review. Clin Exp Ophthalmol. 2014;42:4–12.

    Article  PubMed  Google Scholar 

  23. Boutboul S, Black GC, Moore JE, et al. A subset of patients with epithelial basement membrane corneal dystrophy have mutations in TGFBI/BIGH3. Hum Mutat. 2006;27:553–7.

    Article  CAS  PubMed  Google Scholar 

  24. Lisch W, Bron AJ, Munier FL, et al. Franceschetti hereditary recurrent corneal erosion. Am J Ophthalmol. 2012;153:1073–81.e4.

    Article  Google Scholar 

  25. Wittebol-Post D, van Bijsterveld OP, Delleman JW. Meesmann’s epithelial dystrophy of the cornea. Biometrics and a hypothesis. Ophthalmologica. 1987;194:44–9.

    Article  CAS  PubMed  Google Scholar 

  26. Stocker FW, Holt LB. A rare form of hereditary epithelial dystrophy of the cornea: a genetic, clinical, and pathologic study. Trans Am Ophthalmol Soc. 1954;52:133–44.

    PubMed  PubMed Central  Google Scholar 

  27. Klintworth GK. Corneal dystrophies. Orphanet J Rare Dis. 2009;4:7. https://doi.org/10.1186/1750-1172-4-7.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Alvarez-Fischer M, de Toledo JA, Barraquer RI. Lisch corneal dystrophy. Cornea. 2005;24:494–5.

    Article  PubMed  Google Scholar 

  29. Afshari NA, Mullally JE, Afshari MA, et al. Survey of patients with granular, lattice, avellino, and Reis-Bucklers corneal dystrophies for mutations in the BIGH3 and gelsolin genes. Arch Ophthalmol. 2001;119:16–22.

    CAS  PubMed  Google Scholar 

  30. Kuchle M, Green WR, Volcker HE, Barraquer J. Reevaluation of corneal dystrophies of Bowman’s layer and the anterior stroma (Reis-Bucklers and Thiel-Behnke types): a light and electron microscopic study of eight corneas and a review of the literature. Cornea. 1995;14:333–54.

    Article  CAS  PubMed  Google Scholar 

  31. Kurome H, Noda S, Hayasaka S, Setogawa T. A Japanese family with Grayson-Wilbrandt variant of Reis-Bucklers’ corneal dystrophy. Jpn J Ophthalmol. 1993;37:143–7.

    CAS  PubMed  Google Scholar 

  32. Dighiero P, Niel F, Ellies P, et al. Histologic phenotype-genotype correlation of corneal dystrophies associated with eight distinct mutations in the TGFBI gene. Ophthalmology. 2001;108:818–23.

    Article  CAS  PubMed  Google Scholar 

  33. Afshari NA, Igo RP Jr, Morris NJ, et al. Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy. Nat Commun. 2017;8:14898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Moller HU. Granular corneal dystrophy Groenouw type I. Clinical and genetic aspects. Acta ophthalmol Suppl. 1991;198:1–40.

    Google Scholar 

  35. Lyons CJ, McCartney AC, Kirkness CM, Ficker LA, Steele AD, Rice NS. Granular corneal dystrophy. Visual results and pattern of recurrence after lamellar or penetrating keratoplasty. Ophthalmology. 1994;101:1812–7.

    Article  CAS  PubMed  Google Scholar 

  36. Moon JW, Kim SW, Kim TI, Cristol SM, Chung ES, Kim EK. Homozygous granular corneal dystrophy type II (Avellino corneal dystrophy): natural history and progression after treatment. Cornea. 2007;26:1095–100.

    Article  PubMed  Google Scholar 

  37. Szentmary N, Seitz B, Langenbucher A, Schlotzer-Schrehardt U, Hofmann-Rummelt C, Naumann GO. Histologic and ultrastructural changes in corneas with granular and macular dystrophy after excimer laser phototherapeutic keratectomy. Cornea. 2006;25:257–63.

    Article  PubMed  Google Scholar 

  38. Roh MI, Chung SH, Stulting RD, Kim WC, Kim EK. Preserved peripheral corneal clarity after surgical trauma in patients with Avellino corneal dystrophy. Cornea. 2006;25:497–8.

    Article  PubMed  Google Scholar 

  39. Klintworth GK, Smith CF, Bowling BL. CHST6 mutations in North American subjects with macular corneal dystrophy: a comprehensive molecular genetic review. Mol Vis. 2006;12:159–76.

    CAS  PubMed  Google Scholar 

  40. Jiao X, Munier FL, Schorderet DF, et al. Genetic linkage of Francois-Neetens fleck (mouchetee) corneal dystrophy to chromosome 2q35. Hum Genet. 2003;112:593–9.

    CAS  PubMed  Google Scholar 

  41. Li S, Tiab L, Jiao X, et al. Mutations in PIP5K3 are associated with Francois-Neetens mouchetee fleck corneal dystrophy. Am J Hum Genet. 2005;77:54–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Weiss JS. Schnyder’s dystrophy of the cornea. A Swede-Finn connection. Cornea. 1992;11:93–101.

    Article  CAS  PubMed  Google Scholar 

  43. Weiss JS. Visual morbidity in thirty-four families with Schnyder crystalline corneal dystrophy (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2007;105:616–48.

    PubMed  PubMed Central  Google Scholar 

  44. Bredrup C, Knappskog PM, Majewski J, Rodahl E, Boman H. Congenital stromal dystrophy of the cornea caused by a mutation in the decorin gene. Invest Ophthalmol Vis Sci. 2005;46:420–6.

    Article  PubMed  Google Scholar 

  45. Johnson AT, Folberg R, Vrabec MP, Florakis GJ, Stone EM, Krachmer JH. The pathology of posterior amorphous corneal dystrophy. Ophthalmology. 1990;97:104–9.

    Article  CAS  PubMed  Google Scholar 

  46. Moshegov CN, Hoe WK, Wiffen SJ, Daya SM. Posterior amorphous corneal dystrophy. A new pedigree with phenotypic variation. Ophthalmology. 1996;103:474–8.

    Article  CAS  PubMed  Google Scholar 

  47. Jiao X, Sultana A, Garg P, et al. Autosomal recessive corneal endothelial dystrophy (CHED2) is associated with mutations in SLC4A11. J Med Genet. 2007;44:64–8.

    Article  CAS  PubMed  Google Scholar 

  48. Aldave AJ, Yellore VS, Principe AH, et al. Candidate gene screening for posterior polymorphous dystrophy. Cornea. 2005;24:151–5.

    Article  PubMed  Google Scholar 

  49. Cibis GW, Krachmer JA, Phelps CD, Weingeist TA. The clinical spectrum of posterior polymorphous dystrophy. Arch Ophthalmol. 1977;95:1529–37.

    Article  CAS  PubMed  Google Scholar 

  50. Gottsch JD, Zhang C, Sundin OH, Bell WR, Stark WJ, Green WR. Fuchs corneal dystrophy: aberrant collagen distribution in an L450W mutant of the COL8A2 gene. Invest Ophthalmol Vis Sci. 2005;46:4504–11.

    Article  PubMed  Google Scholar 

  51. Baratz KH, Tosakulwong N, Ryu E, et al. E2-2 protein and Fuchs’s corneal dystrophy. N Engl J Med. 2010;363:1016–24.

    Article  CAS  PubMed  Google Scholar 

  52. Cabral T, DiCarlo JE, Justus S, Sengillo JD, Xu Y, Tsang SH. CRISPR applications in ophthalmologic genome surgery. Curr Opin Ophthalmol. 2017;28:252–9.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Christie KA, Courtney DG, DeDionisio LA, et al. Towards personalised allele-specific CRISPR gene editing to treat autosomal dominant disorders. Sci Rep. 2017;7:16174.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  54. Zhu AY, Jaskula-Ranga V, Jun AS. Gene editing as a potential therapeutic solution for fuchs endothelial corneal dystrophy: the future is clearer. JAMA Ophthalmol. 2018;136:969–70.

    Article  PubMed  Google Scholar 

  55. Dunbar CE, High KA, Joung JK, Kohn DB, Ozawa K, Sadelain M. Gene therapy comes of age. Science (New York, NY). 2018;359:1–12.

    Article  PubMed  CAS  Google Scholar 

  56. Zhao JJ, Afshari NA. Generation of human corneal endothelial cells via in vitro ocular lineage restriction of pluripotent stem cells. Invest Ophthalmol Vis Sci. 2016;57:6878–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Meekins LC, Rosado-Adames N, Maddala R, Zhao JJ, Rao PV, Afshari NA. Corneal endothelial cell migration and proliferation enhanced by rho kinase (ROCK) inhibitors in in vitro and in vivo models. Invest Ophthalmol Vis Sci. 2016;57:6731–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Okumura N, Kinoshita S, Koizumi N. Application of rho kinase inhibitors for the treatment of corneal endothelial diseases. J Ophthalmol. 2017;2017:2646904.

    PubMed  PubMed Central  Google Scholar 

  59. He S, Li X, Chan N, Hinton DR. Review: epigenetic mechanisms in ocular disease. Mol Vis. 2013;19:665–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. McMonnies CW. Epigenetic mechanisms might help explain environmental contributions to the pathogenesis of keratoconus. Eye Contact Lens. 2014;40:371–5.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Shiley Eye Institute University of California, San Diego, La Jolla, CA, USA

    Natalie A. Afshari & Ashlie Bernhisel

Authors
  1. Natalie A. Afshari
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  2. Ashlie Bernhisel
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Correspondence to Natalie A. Afshari .

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Editors and Affiliations

  1. Louis Block Professor Chair, Department of Ophthalmology and Visual Science, The University of Chicago Medicine & Biological Sciences, Chicago, IL, USA

    Kathryn Colby

  2. Claes H. Dohlman Professor of Ophthalmology, Harvard Medical School, Cornea & Refractive Surgery, Massachusetts Eye & Ear, Boston, MA, USA

    Reza Dana

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Afshari, N.A., Bernhisel, A. (2020). Genetics of Corneal Disease. In: Colby, K., Dana, R. (eds) Foundations of Corneal Disease. Springer, Cham. https://doi.org/10.1007/978-3-030-25335-6_22

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  • DOI: https://doi.org/10.1007/978-3-030-25335-6_22

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