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Corneal dystrophies

Nature Reviews Disease Primers volume 6, Article number: 46 (2020) Cite this article

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Abstract

Corneal dystrophies are broadly defined as inherited disorders that affect any layer of the cornea and are usually progressive, bilateral conditions that do not have systemic effects. The 2015 International Classification of Corneal Dystrophies classifies corneal dystrophies into four classes: epithelial and subepithelial dystrophies, epithelial–stromal TGFBI dystrophies, stromal dystrophies and endothelial dystrophies. Whereas some corneal dystrophies may result in few or mild symptoms and morbidity throughout a patient’s lifetime, others may progress and eventually result in substantial visual and ocular disturbances that require medical or surgical intervention. Corneal transplantation, either with full-thickness or partial-thickness donor tissue, may be indicated for patients with advanced corneal dystrophies. Although corneal transplantation techniques have improved considerably over the past two decades, these surgeries are still associated with postoperative risks of disease recurrence, graft failure and other complications that may result in blindness. In addition, a global shortage of cadaveric corneal graft tissue critically limits accessibility to corneal transplantation in some parts of the world. Ongoing advances in gene therapy, regenerative therapy and cell augmentation therapy may eventually result in the development of alternative, novel treatments for corneal dystrophies, which may substantially improve the quality of life of patients with these disorders.

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Fig. 1: Examples of corneal dystrophies.
Fig. 2: Ophthalmic imaging modalities.
Fig. 3: Corneal transplantation techniques.
Fig. 4: Complications of corneal dystrophies and their treatment.
Fig. 5: Current and future therapeutic modalities for corneal dystrophies.

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References

  1. Qazi, Y., Wong, G., Monson, B., Stringham, J. & Ambati, B. K. Corneal transparency: genesis, maintenance and dysfunction. Brain Res. Bull. 81, 198–210 (2010).

    Article  PubMed  Google Scholar 

  2. Maurice, D. M. The structure and transparency of the cornea. J. Physiol. 136, 263–286 (1957).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. DelMonte, D. W. & Kim, T. Anatomy and physiology of the cornea. J. Cataract Refract. Surg. 37, 588–598 (2011).

    Article  PubMed  Google Scholar 

  4. Weiss, J. S. Visual morbidity in thirty-four families with Schnyder crystalline corneal dystrophy (an American Ophthalmological Society thesis). Trans. Am. Ophthalmol. Soc. 105, 616–648 (2007). The largest collection of SCD cases published to date.

    PubMed  PubMed Central  Google Scholar 

  5. Weiss, J. S. et al. IC3D classification of corneal dystrophies — edition 2. Cornea 34, 117–159 (2015). This manuscript describes the latest classification system for corneal dystrophies, published and endorsed by the Cornea Society.

    Article  PubMed  Google Scholar 

  6. Soh, Y. Q. et al. Predicative factors for corneal endothelial cell migration. Investig. Ophthalmol. Vis. Sci. 57, 338 (2016).

    Article  Google Scholar 

  7. Soh, Y. Q. & Mehta, J. S. Regenerative therapy for Fuchs endothelial corneal dystrophy. Cornea 37, 523–527 (2018).

    Article  PubMed  Google Scholar 

  8. Bhogal, M., Lwin, C. N., Seah, X.-Y., Peh, G. & Mehta, J. S. Allogeneic Descemet’s membrane transplantation enhances corneal endothelial monolayer formation and restores functional integrity following Descemet’s stripping. Invest. Ophthalmol. Vis. Sci. 58, 4249–4260 (2017).

    Article  CAS  PubMed  Google Scholar 

  9. Peh, G. S. L. et al. Functional evaluation of two corneal endothelial cell-based therapies: tissue-engineered construct and cell injection. Sci. Rep. 9, 6087 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Kinoshita, S. et al. Injection of cultured cells with a ROCK inhibitor for bullous keratopathy. N. Engl. J. Med. 378, 995–1003 (2018). First-in-human trial describing the successful treatment of bullous keratopathy, including cases of FECD, with intracameral injection of cultivated human corneal endothelial cells.

    Article  CAS  PubMed  Google Scholar 

  11. Yam, G. H.-F. et al. Safety and feasibility of intrastromal injection of cultivated human corneal stromal keratocytes as cell-based therapy for corneal opacities. Invest. Ophthalmol. Vis. Sci. 59, 3340–3354 (2018).

    Article  CAS  PubMed  Google Scholar 

  12. Peh, G. S. L. et al. Regulatory compliant tissue-engineered human corneal endothelial grafts restore corneal function of rabbits with bullous keratopathy. Sci. Rep. 7, 14149 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Mehta, J. S., Kocaba, V. & Soh, Y. Q. The future of keratoplasty: cell-based therapy, regenerative medicine, bioengineering keratoplasty, gene therapy. Curr. Opin. Ophthalmol. 30, 286–291 (2019).

    Article  PubMed  Google Scholar 

  14. Soh, Y. Q. et al. Trinucleotide repeat expansion length as a predictor of the clinical progression of Fuchs’ endothelial corneal dystrophy. PLoS One 14, e0210996 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Taketani, Y. et al. Repair of the TGFBI gene in human corneal keratocytes derived from a granular corneal dystrophy patient via CRISPR/Cas9-induced homology-directed repair. Sci. Rep. 7, 16713 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Boutboul, S. et al. A subset of patients with epithelial basement membrane corneal dystrophy have mutations in TGFBI/BIGH3. Hum. Mutat. 27, 553–557 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Reidy, J. J., Paulus, M. P. & Gona, S. Recurrent erosions of the cornea: epidemiology and treatment. Cornea 19, 767–771 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Suri, K. et al. Demographic patterns and treatment outcomes of patients with recurrent corneal erosions related to trauma and epithelial and Bowman layer disorders. Am. J. Ophthalmol. 156, 1082–1087.e2 (2013).

    Article  PubMed  Google Scholar 

  19. Waring, G. O., Rodrigues, M. M. & Laibson, P. R. Corneal dystrophies. I. Dystrophies of the epithelium, Bowman’s layer and stroma. Surv. Ophthalmol. 23, 71–122 (1978).

    Article  PubMed  Google Scholar 

  20. Werblin, T. P., Hirst, L. W., Stark, W. J. & Maumenee, I. H. Prevalence of map-dot-fingerprint changes in the cornea. Br. J. Ophthalmol. 65, 401–409 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bozkurt, B. & Irkec, M. In vivo laser confocal microscopic findings in patients with epithelial basement membrane dystrophy. Eur. J. Ophthalmol. 19, 348–354 (2009).

    Article  PubMed  Google Scholar 

  22. Kaza, H., Barik, M. R., Reddy, M. M., Mittal, R. & Das, S. Gelatinous drop-like corneal dystrophy: a review. Br. J. Ophthalmol. 101, 10–15 (2017).

    Article  PubMed  Google Scholar 

  23. Fujiki, K., Nakayasu, K. & Kanai, A. Corneal dystrophies in Japan. J. Hum. Genet. 46, 431–435 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Kawasaki, S. & Kinoshita, S. Clinical and basic aspects of gelatinous drop-like corneal dystrophy. Dev. Ophthalmol. 48, 97–115 (2011).

    Article  PubMed  Google Scholar 

  25. Song, Y. et al. Prevalence of transforming growth factor β-induced gene corneal dystrophies in Chinese refractive surgery candidates. J. Cataract Refract. Surg. 43, 1489–1494 (2017).

    Article  PubMed  Google Scholar 

  26. Mashima, Y. et al. Association of autosomal dominantly inherited corneal dystrophies with BIGH3 gene mutations in Japan. Am. J. Ophthalmol. 130, 516–517 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Cho, K. J. et al. TGFBI gene mutations in a Korean population with corneal dystrophy. Mol. Vis. 18, 2012–2021 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Lee, J. H. et al. Prevalence of granular corneal dystrophy type 2 (Avellino corneal dystrophy) in the Korean population. Ophthalmic Epidemiol. 17, 160–165 (2010).

    Article  PubMed  Google Scholar 

  29. Musch, D. C., Niziol, L. M., Stein, J. D., Kamyar, R. M. & Sugar, A. Prevalence of corneal dystrophies in the united states: estimates from claims data. Invest. Ophthalmol. Vis. Sci. 52, 6959–6963 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Chao-Shern, C. et al. Evaluation of TGFBI corneal dystrophy and molecular diagnostic testing. Eye 33, 874–881 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Munier, F. L. et al. BIGH3 mutation spectrum in corneal dystrophies. Invest. Ophthalmol. Vis. Sci. 43, 949–954 (2002).

    PubMed  Google Scholar 

  32. Han, K. E. et al. Pathogenesis and treatments of TGFBI corneal dystrophies. Prog. Retinal Eye Res. 50, 67–88 (2016).

    Article  CAS  Google Scholar 

  33. Kheir, V., Cortés-González, V., Zenteno, J. C. & Schorderet, D. F. Mutation update: TGFBI pathogenic and likely pathogenic variants in corneal dystrophies. Hum. Mutat. 40, 675–693 (2019).

    Article  CAS  PubMed  Google Scholar 

  34. Munier, F. L. et al. Kerato-epithelin mutations in four 5q31-linked corneal dystrophies. Nat. Genet. 15, 247–251 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Pampukha, V. M., Drozhyna, G. I. & Livshits, L. A. TGFBI gene mutation analysis in families with hereditary corneal dystrophies from Ukraine. OPH 218, 411–414 (2004).

    CAS  Google Scholar 

  36. Al-Arfai, K. M., Yassin, S. A., Al-Beshri, A. S., Al-Jindan, M. Y. & Al-Tamimi, E. R. Indications and techniques employed for keratoplasty in the Eastern province of Saudi Arabia: 6 years of experience. Ann. Saudi Med. 35, 387–393 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Eye Bank Association of America. 2018 Eye Banking Statistical Report 1–108 (Eye Bank Association of America, 2019).

  38. Eye Bank Association of America. 2016 Eye Banking Statistical Report 1–99 (Eye Bank Association of America, 2016).

  39. Saadat, M., Ansari-Lari, M. & Farhud, D. D. Consanguineous marriage in Iran. Ann. Hum. Biol. 31, 263–269 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Zare, M. et al. Changing indications and surgical techniques for corneal transplantation between 2004 and 2009 at a tertiary referral center. Middle East Afr. J. Ophthalmol. 19, 323–329 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Zare, M. et al. Indications for corneal transplantation at a tertiary referral center in Tehran. J. Ophthalmic Vis. Res. 5, 82–86 (2010).

    PubMed  PubMed Central  Google Scholar 

  42. Yaylacioglu Tuncay, F. et al. Genetic analysis of CHST6 and TGFBI in Turkish patients with corneal dystrophies: five novel variations in CHST6. Mol. Vis. 22, 1267–1279 (2016).

    PubMed  PubMed Central  Google Scholar 

  43. Warren, J. F. et al. Novel mutations in the CHST6 gene associated with macular corneal dystrophy in Southern India. Arch. Ophthalmol. 121, 1608–1612 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Sultana, A., Klintworth, G. K., Thonar, E. J.-M. A., Vemuganti, G. K. & Kannabiran, C. Immunophenotypes of macular corneal dystrophy in India and correlation with mutations in CHST6. Mol. Vis. 15, 319–325 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Jonasson, F., Johannsson, J. H., Garner, A. & Rice, N. S. Macular corneal dystrophy in Iceland. Eye 3 (Pt 4), 446–454 (1989).

    Article  PubMed  Google Scholar 

  46. Jonasson, F. et al. Macular corneal dystrophy in Iceland. A clinical, genealogic, and immunohistochemical study of 28 patients. Ophthalmology 103, 1111–1117 (1996).

    Article  CAS  PubMed  Google Scholar 

  47. Schnyder, W. F. Mitteilung über einen neuen typus von familiärer hornhauterkrankung [German]. Schweiz. Med. Wschr. 10, 559–571 (1929).

    Google Scholar 

  48. Schnyder, W. F. Scheibenförmige kristalleinlagerungen in der hornhautmitte als erbleiden [German]. KIin. Monatsbl. Augenheilkd. 103, 494–502 (1939).

    Google Scholar 

  49. Weiss, J. S. Schnyder’s dystrophy of the cornea. A Swede-Finn connection. Cornea 11, 93–101 (1992).

    Article  CAS  PubMed  Google Scholar 

  50. Nickerson, M. L. et al. The UBIAD1 prenyltransferase links menaquione-4 synthesis to cholesterol metabolic enzymes. Hum. Mutat. 34, 317–329 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Yamada, M., Mochizuki, H., Kamata, Y., Nakamura, Y. & Mashima, Y. Quantitative analysis of lipid deposits from Schnyder’s corneal dystrophy. Br. J. Ophthalmol. 82, 444–447 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Weiss, J. S. Schnyder corneal dystrophy. Curr. Opin. Ophthalmol. 20, 292–298 (2009).

    Article  PubMed  Google Scholar 

  53. Hung, C., Ayabe, R. I., Wang, C., Frausto, R. F. & Aldave, A. J. Pre-Descemet corneal dystrophy and X-linked ichthyosis associated with deletion of Xp22.31 containing the STS gene. Cornea 32, 1283–1287 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Costagliola, C., Fabbrocini, G., Illiano, G. M., Scibelli, G. & Delfino, M. Ocular findings in X-linked ichthyosis: a survey on 38 cases. Ophthalmologica 202, 152–155 (1991).

    Article  CAS  PubMed  Google Scholar 

  55. Soh, Y. Q., Peh, G. S. & Mehta, J. S. Evolving therapies for Fuchs’ endothelial dystrophy. Regen. Med. 13, 97–115 (2018).

    Article  CAS  PubMed  Google Scholar 

  56. Luther, M. et al. TGC repeats in Intron 2 of the TCF4 gene have a good predictive power regarding to Fuchs endothelial corneal dystrophy [German]. Klin. Monbl. Augenheilkd. 233, 187–194 (2016).

    CAS  PubMed  Google Scholar 

  57. Afshari, N. A. et al. Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy. Nat. Commun. 8, 14898 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Soh, Y. Q., Kocaba, V., Pinto, M. & Mehta, J. S. Fuchs endothelial corneal dystrophy and corneal endothelial diseases: East meets West. Eye 34, 427–441 (2020).

    Article  CAS  PubMed  Google Scholar 

  59. Liu, C. et al. Ultraviolet A light induces DNA damage and estrogen-DNA adducts in Fuchs endothelial corneal dystrophy causing females to be more affected. Proc. Natl Acad. Sci. USA 117, 573–583 (2020).

    Article  CAS  PubMed  Google Scholar 

  60. Jurkunas, U. V. Fuchs endothelial corneal dystrophy through the prism of oxidative stress. Cornea 37 (Suppl. 1), 50–54 (2018).

    Article  Google Scholar 

  61. Zhang, X. et al. Association of smoking and other risk factors with Fuchs’ endothelial corneal dystrophy severity and corneal thickness. Invest. Ophthalmol. Vis. Sci. 54, 5829–5835 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Zoega, G. M. et al. Prevalence and risk factors for cornea guttata in the Reykjavik eye study. Ophthalmology 113, 565–569 (2006).

    Article  PubMed  Google Scholar 

  63. Krachmer, J. H., Purcell, J. J. Jr., Young, C. W. & Bucher, K. D. Corneal endothelial dystrophy. A study of 64 families. Arch. Ophthalmol. 96, 2036–2039 (1978).

    Article  CAS  PubMed  Google Scholar 

  64. Kitagawa, K. et al. Prevalence of primary cornea guttata and morphology of corneal endothelium in aging Japanese and Singaporean subjects. Ophthalmic Res. 34, 135–138 (2002).

    Article  PubMed  Google Scholar 

  65. Davidson, A. E. et al. Autosomal-dominant corneal endothelial dystrophies CHED1 and PPCD1 are allelic disorders caused by non-coding mutations in the promoter of OVOL2. Am. J. Hum. Genet. 98, 75–89 (2016).

    Article  CAS  PubMed  Google Scholar 

  66. Hong, T. et al. An Ovol2-Zeb1 mutual inhibitory circuit governs bidirectional and multi-step transition between epithelial and mesenchymal states. PLoS Computational Biol. 11, e1004569 (2015).

    Article  CAS  Google Scholar 

  67. Biswas, S. et al. Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy. Hum. Mol. Genet. 10, 2415–2423 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Kobayashi, A. et al. Analysis of COL8A2 gene mutation in Japanese patients with Fuchs’ endothelial dystrophy and posterior polymorphous dystrophy. Jpn. J. Ophthalmol. 48, 195–198 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Yellore, V. S. et al. No pathogenic mutations identified in the COL8A2 gene or four positional candidate genes in patients with posterior polymorphous corneal dystrophy. Invest. Ophthalmol. Vis. Sci. 46, 1599–1603 (2005).

    Article  PubMed  Google Scholar 

  70. Frausto, R. F. et al. ZEB1 insufficiency causes corneal endothelial cell state transition and altered cellular processing. PLoS One 14, e0218279 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Liskova, P. et al. Ectopic GRHL2 expression due to non-coding mutations promotes cell state transition and causes posterior polymorphous corneal dystrophy 4. Am. J. Hum. Genet. 102, 447–459 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Chung, D. D. et al. Alterations in GRHL2-OVOL2-ZEB1 axis and aberrant activation of Wnt signaling lead to altered gene transcription in posterior polymorphous corneal dystrophy. Exp. Eye Res. 188, 107696 (2019).

    Article  CAS  PubMed  Google Scholar 

  73. Liskova, P. et al. High prevalence of posterior polymorphous corneal dystrophy in the Czech Republic; linkage disequilibrium mapping and dating an ancestral mutation. PLoS One 7, e45495 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Schmid, E. et al. A new, X-linked endothelial corneal dystrophy. Am. J. Ophthalmol. 141, 478–487 (2006).

    Article  PubMed  Google Scholar 

  75. Gipson, I. K., Spurr-Michaud, S. J. & Tisdale, A. S. Anchoring fibrils form a complex network in human and rabbit cornea. Invest. Ophthalmol. Vis. Sci. 28, 212–220 (1987).

    CAS  PubMed  Google Scholar 

  76. Kabosova, A. et al. Compositional differences between infant and adult human corneal basement membranes. Invest. Ophthalmol. Vis. Sci. 48, 4989–4999 (2007).

    Article  PubMed  Google Scholar 

  77. Torricelli, A. A. M., Singh, V., Santhiago, M. R. & Wilson, S. E. The corneal epithelial basement membrane: structure, function, and disease. Invest. Ophthalmol. Vis. Sci. 54, 6390–6400 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Legrand, J. Dystrophie épithéliale cornéenne récidivante familiale [French]. Bull. Soc. Ophtalmol. 5, 384–387 (1963).

    Google Scholar 

  79. Remler, O. Hereditary recurrent erosion of the cornea [German]. Klin. Monatsbl. Augenheilkd. 183, 59 (1983).

    Article  CAS  PubMed  Google Scholar 

  80. Shindo, S. Familial recurrent corneal erosion [Japanese]. Nippon Ganka Gakkai Zasshi 72, 998–1004 (1968).

    CAS  PubMed  Google Scholar 

  81. Wales, H. J. A family history of corneal erosions. Trans. Ophthalmol. Soc. N. Z. 8, 77–78 (1955).

    CAS  PubMed  Google Scholar 

  82. Franceschetti, A. Hereditäre rezidivierende Erosion der Hornhaut. Z Augenheilk 66, 309–316 (1928).

    Google Scholar 

  83. Lisch, W. et al. Franceschetti hereditary recurrent corneal erosion. Am. J. Ophthalmol. 153, 1073–1081.e4 (2012).

    Article  PubMed  Google Scholar 

  84. Hammar, B., Björck, E., Lagerstedt, K., Dellby, A. & Fagerholm, P. A new corneal disease with recurrent erosive episodes and autosomal-dominant inheritance. Acta Ophthalmol. 86, 758–763 (2008).

    Article  PubMed  Google Scholar 

  85. Hammar, B. et al. Dystrophia Smolandiensis: a novel morphological picture of recurrent corneal erosions. Acta Ophthalmol. 88, 394–400 (2010).

    Article  PubMed  Google Scholar 

  86. Hammar, B. et al. Dystrophia Helsinglandica: a new type of hereditary corneal recurrent erosions with late subepithelial fibrosis. Acta Ophthalmol. 87, 659–665 (2009).

    Article  PubMed  Google Scholar 

  87. Neira, W. et al. Dystrophia Helsinglandica-corneal morphology, topography and sensitivity in a hereditary corneal disease with recurrent erosive episodes. Acta Ophthalmol. 88, 401–406 (2010).

    Article  PubMed  Google Scholar 

  88. Kuwabara, T. & Ciccarelli, E. C. Meesmann’s corneal dystrophy: a pathological study. Arch. Ophthalmol. 71, 676–682 (1964).

    Article  Google Scholar 

  89. Irvine, A. D. et al. Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann’s corneal dystrophy. Nat. Genet. 16, 184–187 (1997).

    Article  CAS  PubMed  Google Scholar 

  90. Allen, E. H. A. et al. Keratin 12 missense mutation induces the unfolded protein response and apoptosis in Meesmann epithelial corneal dystrophy. Hum. Mol. Genet. 25, 1176–1191 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. McLean, W. H. I. & Moore, C. B. T. Keratin disorders: from gene to therapy. Hum. Mol. Genet. 20, R189–R197 (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Lisch, W. & Weiss, J. S. Clinical and genetic update of corneal dystrophies. Exp. Eye Res. 186, 107715 (2019).

    Article  CAS  PubMed  Google Scholar 

  93. Lisch, W. et al. Lisch corneal dystrophy is genetically distinct from Meesmann corneal dystrophy and maps to Xp22.3. Am. J. Ophthalmol. 130, 461–468 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Jongkhajornpong, P. et al. Novel TACSTD2 mutation in gelatinous drop-like corneal dystrophy. Hum. Genome Var. 2, 15047 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Tsujikawa, M. et al. Identification of the gene responsible for gelatinous drop-like corneal dystrophy. Nat. Genet. 21, 420–423 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. Kinoshita, S. et al. Epithelial barrier function and ultrastructure of gelatinous drop-like corneal dystrophy. Cornea 19, 551–555 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Nakatsukasa, M. et al. Tumor-associated calcium signal transducer 2 is required for the proper subcellular localization of claudin 1 and 7: implications in the pathogenesis of gelatinous drop-like corneal dystrophy. Am. J. Pathol. 177, 1344–1355 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Tsujikawa, M. Gelatinous drop-like corneal dystrophy. Cornea 31 (Suppl. 1), 37–40 (2012).

    Article  Google Scholar 

  99. McDougall, A. R. A., Tolcos, M., Hooper, S. B., Cole, T. J. & Wallace, M. J. Trop2: from development to disease. Dev. Dyn. 244, 99–109 (2015).

    Article  CAS  PubMed  Google Scholar 

  100. Skonier, J. et al. cDNA cloning and sequence analysis of βig-h3, a novel gene induced in a human adenocarcinoma cell line after treatment with transforming growth factor-β. DNA Cell Biol. 11, 511–522 (1992).

    Article  CAS  PubMed  Google Scholar 

  101. Ma, C. et al. Extracellular matrix protein βig-h3/TGFBI promotes metastasis of colon cancer by enhancing cell extravasation. Genes. Dev. 22, 308–321 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Zajchowski, D. A. et al. Identification of gene expression profiles that predict the aggressive behavior of breast cancer cells. Cancer Res. 61, 5168–5178 (2001).

    CAS  PubMed  Google Scholar 

  103. Park, S.-Y., Jung, M.-Y. & Kim, I.-S. Stabilin-2 mediates homophilic cell-cell interactions via its FAS1 domains. FEBS Lett. 583, 1375–1380 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. Korvatska, E. et al. On the role of kerato-epithelin in the pathogenesis of 5q31-linked corneal dystrophies. Invest. Ophthalmol. Vis. Sci. 40, 2213–2219 (1999).

    CAS  PubMed  Google Scholar 

  105. Selkoe, D. J. Presenilin, Notch, and the genesis and treatment of Alzheimer’s disease. Proc. Natl Acad. Sci. USA 98, 11039–11041 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Huang, W.-J., Zhang, X. & Chen, W.-W. Role of oxidative stress in Alzheimer’s disease. Biomed. Rep. 4, 519–522 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lim, K. L. et al. Parkin mediates nonclassical, proteasomal-independent ubiquitination of synphilin-1: implications for Lewy body formation. J. Neurosci. 25, 2002–2009 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Chung, K. K. et al. Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat. Med. 7, 1144–1150 (2001).

    Article  CAS  PubMed  Google Scholar 

  109. Scott, J. E. & Haigh, M. Identification of specific binding sites for keratan sulphate proteoglycans and chondroitin-dermatan sulphate proteoglycans on collagen fibrils in cornea by the use of cupromeronic blue in ‘critical-electrolyte-concentration’ techniques. Biochem. J. 253, 607–610 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Lewis, D. et al. Ultrastructural localization of sulfated and unsulfated keratan sulfate in normal and macular corneal dystrophy type I. Glycobiology 10, 305–312 (2000).

    Article  CAS  PubMed  Google Scholar 

  111. Zhang, J. et al. A comprehensive evaluation of 181 reported CHST6 variants in patients with macular corneal dystrophy. Aging 11, 1019–1029 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Musselmann, K. & Hassell, J. R. Focus on molecules: CHST6 (carbohydrate sulfotransferase 6; corneal N-acetylglucosamine-6-sulfotransferase). Exp. Eye Res. 83, 707–708 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Hassell, J. R., Newsome, D. A., Krachmer, J. H. & Rodrigues, M. M. Macular corneal dystrophy: failure to synthesize a mature keratan sulfate proteoglycan. Proc. Natl Acad. Sci USA 77, 3705–3709 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Aggarwal, S., Peck, T., Golen, J. & Karcioglu, Z. A. Macular corneal dystrophy: a review. Surv. Ophthalmol. 63, 609–617 (2018).

    Article  PubMed  Google Scholar 

  115. Klintworth, G. K. & Vogel, F. S. Macular corneal dystrophy. An inherited acid mucopolysaccharide storage disease of the corneal fibroblast. Am. J. Pathol. 45, 565–586 (1964).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Orr, A. et al. Mutations in the UBIAD1 gene, encoding a potential prenyltransferase, are causal for Schnyder crystalline corneal dystrophy. PLoS One 2, e685 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Nakagawa, K. et al. Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. Nature 468, 117–121 (2010).

    Article  CAS  PubMed  Google Scholar 

  118. Jo, Y. et al. Schnyder corneal dystrophy-associated UBIAD1 inhibits ER-associated degradation of HMG CoA reductase in mice. Elife 8, e44396 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Weller, R. O. & Rodger, F. C. Crystalline stromal dystrophy: histochemistry and ultrastructure of the cornea. Br. J. Ophthalmol. 64, 46–52 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Hariri, M. et al. Biogenesis of multilamellar bodies via autophagy. Mol. Biol. Cell 11, 255–268 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Weiss, J. S. & Khemichian, A. J. Differential diagnosis of Schnyder corneal dystrophy. Dev. Ophthalmol. 48, 67–96 (2011).

    Article  PubMed  Google Scholar 

  122. Zhang, W. et al. Decorin is a pivotal effector in the extracellular matrix and tumour microenvironment. Oncotarget 9, 5480–5491 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Mohan, R. R., Tovey, J. C. K., Gupta, R., Sharma, A. & Tandon, A. Decorin biology, expression, function and therapy in the cornea. Curr. Mol. Med. 11, 110–128 (2011).

    Article  CAS  PubMed  Google Scholar 

  124. Bredrup, C., Knappskog, P. M., Majewski, J., Rødahl, E. & Boman, H. Congenital stromal dystrophy of the cornea caused by a mutation in the decorin gene. Invest. Ophthalmol. Vis. Sci. 46, 420–426 (2005).

    Article  PubMed  Google Scholar 

  125. Kamma-Lorger, C. S. et al. Role of decorin core protein in collagen organisation in congenital stromal corneal dystrophy (CSCD). PLoS One 11, e0147948 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Nicholson, D. H., Green, W. R., Cross, H. E., Kenyon, K. R. & Massof, D. A clinical and histopathological study of François-Neetens speckled corneal dystrophy. Am. J. Ophthalmol. 83, 554–560 (1977).

    Article  CAS  PubMed  Google Scholar 

  127. Gee, J. A. et al. Identification of novel PIKFYVE gene mutations associated with Fleck corneal dystrophy. Mol. Vis. 21, 1093–1100 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Kawasaki, S. et al. A novel mutation (p.Glu1389AspfsX16) of the phosphoinositide kinase, FYVE finger containing gene found in a Japanese patient with fleck corneal dystrophy. Mol. Vis. 18, 2954–2960 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Li, S. et al. Mutations in PIP5K3 are associated with François-Neetens Mouchetée fleck corneal dystrophy. Am. J. Hum. Genet. 77, 54–63 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Kim, M. J. et al. Posterior amorphous corneal dystrophy is associated with a deletion of small leucine-rich proteoglycans on chromosome 12. PLoS One 9, e95037 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Aldave, A. J. et al. Linkage of posterior amorphous corneal dystrophy to chromosome 12q21.33 and exclusion of coding region mutations in KERA, LUM, DCN, and EPYC. Invest. Ophthalmol. Vis. Sci. 51, 4006–4012 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Fernandez-Sasso, D., Acosta, J. E. & Malbran, E. Punctiform and polychromatic pre-Descemet’s dominant corneal dystrophy. Br. J. Ophthalmol. 63, 336–338 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Alió Del Barrio, J. L. et al. Punctiform and polychromatic pre-Descemet corneal dystrophy: clinical evaluation and identification of the genetic basis. Am. J. Ophthalmol. 212, 88–97 (2020).

    Article  PubMed  CAS  Google Scholar 

  134. Henríquez-Recine, M. A. et al. Heredity and in vivo confocal microscopy of punctiform and polychromatic pre-Descemet dystrophy. Graefes Arch. Clin. Exp. Ophthalmol. 256, 1661–1667 (2018).

    Article  PubMed  CAS  Google Scholar 

  135. Curran, R. E., Kenyon, K. R. & Green, W. R. Pre-Descemet’s membrane corneal dystrophy. Am. J. Ophthalmol. 77, 711–716 (1974).

    Article  CAS  PubMed  Google Scholar 

  136. Grayson, M. & Wilbrandt, H. Pre-Descemet dystrophy. Am. J. Ophthalmol. 64, 276–282 (1967).

    Article  CAS  PubMed  Google Scholar 

  137. Alafaleq, M., Georgeon, C., Grieve, K. & Borderie, V. M. Multimodal imaging of pre-Descemet corneal dystrophy. Eur. J. Ophthalmol. https://doi.org/10.1177/1120672119862505 (2019).

    Article  PubMed  Google Scholar 

  138. Kempster, R. C., Hirst, L. W., Cruz de la, Z. & Green, W. R. Clinicopathologic study of the cornea in X-linked Ichthyosis. Arch. Ophthalmol. 115, 409–415 (1997).

    Article  CAS  PubMed  Google Scholar 

  139. Rudolf, M., Grösch, S. & Geerling, G. Recurrent bilateral corneal erosions and opacities in corneal stroma. Pre-Descemet dystrophy in X chromosome recessive ichthyosis [German]. Ophthalmologe 99, 962–963 (2002).

    Article  CAS  PubMed  Google Scholar 

  140. Tiepolo, L. et al. Assignment by deletion mapping of the steroid sulfatase X-linked ichthyosis locus to Xp223. Hum. Genet. 54, 205–206 (1980).

    Article  CAS  PubMed  Google Scholar 

  141. Diociaiuti, A. et al. X-linked ichthyosis: clinical and molecular findings in 35 Italian patients. Exp. Dermatol. 28, 1156–1163 (2019).

    Article  CAS  PubMed  Google Scholar 

  142. Mootha, V. V. et al. TCF4 triplet repeat expansion and nuclear RNA foci in Fuchs’ endothelial corneal dystrophy. Invest. Ophthalmol. Vis. Sci. 56, 2003–2011 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Wieben, E. D. et al. Trinucleotide repeat expansion in the transcription factor 4 (TCF4) gene leads to widespread mRNA splicing changes in Fuchs’ endothelial corneal dystrophy. Invest. Ophthalmol. Vis. Sci. 58, 343–352 (2017). The authors of this paper were the first to describe the strong association between a trinucleotide repeat expansion in TCF4 and FECD; in this paper, they describe the pathophysiological link between the repeat expansion sequence and disease phenotype.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Azizi, B. et al. p53-regulated increase in oxidative-stress-induced apoptosis in Fuchs endothelial corneal dystrophy: a native tissue model. Invest. Ophthalmol. Vis. Sci. 52, 9291–9297 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Jurkunas, U. V., Bitar, M. S., Funaki, T. & Azizi, B. Evidence of oxidative stress in the pathogenesis of Fuchs endothelial corneal dystrophy. Am. J. Pathol. 177, 2278–2289 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Halilovic, A. et al. Menadione-induced DNA damage leads to mitochondrial dysfunction and fragmentation during rosette formation in Fuchs endothelial corneal dystrophy. Antioxid. Redox Signal. 24, 1072–1083 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Benischke, A.-S. et al. Activation of mitophagy leads to decline in Mfn2 and loss of mitochondrial mass in Fuchs endothelial corneal dystrophy. Sci. Rep. 7, 6656 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Miyai, T. et al. Activation of PINK1-Parkin-mediated mitophagy degrades mitochondrial quality control proteins in Fuchs endothelial corneal dystrophy. Am. J. Pathol. 189, 2061–2076 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Matthaei, M. et al. Fuchs endothelial corneal dystrophy: clinical, genetic, pathophysiologic, and therapeutic aspects. Annu. Rev. Vis. Sci. 5, 151–175 (2019).

    Article  PubMed  Google Scholar 

  150. Kim, E. C. et al. Screening and characterization of drugs that protect corneal endothelial cells against unfolded protein response and oxidative stress. Invest. Ophthalmol. Vis. Sci. 58, 892–900 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Toyono, T. et al. MicroRNA-29b overexpression decreases extracellular matrix mRNA and protein production in human corneal endothelial cells. Cornea 35, 1466–1470 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Matthaei, M. et al. Transcript profile of cellular senescence-related genes in Fuchs endothelial corneal dystrophy. Exp. Eye Res. 129, 13–17 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Miyajima, T. et al. Loss of NQO1 generates genotoxic estrogen-DNA adducts in Fuchs endothelial corneal dystrophy. Free. Radic. Biol. Med. 147, 69–79 (2020).

    Article  CAS  PubMed  Google Scholar 

  154. Chaurasia, S., Mittal, R., Bichappa, G., Ramappa, M. & Murthy, S. I. Clinical characterization of posterior polymorphous corneal dystrophy in patients of Indian ethnicity. Int. Ophthalmol. 37, 945–952 (2017).

    Article  PubMed  Google Scholar 

  155. Shiraishi, A., Zheng, X., Sakane, Y., Hara, Y. & Hayashi, Y. In vivo confocal microscopic observations of eyes diagnosed with posterior corneal vesicles. Jpn. J. Ophthalmol. 60, 425–432 (2016).

    Article  PubMed  Google Scholar 

  156. Aldave, A. J., Han, J. & Frausto, R. F. Genetics of the corneal endothelial dystrophies: an evidence-based review. Clin. Genet. 84, 139–119 (2013).

    Article  CAS  Google Scholar 

  157. Patel, S. P. & Parker, M. D. SLC4A11 and the pathophysiology of congenital hereditary endothelial dystrophy. Biomed. Res. Int. 2015, 475392 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Vilas, G. L. et al. Transmembrane water-flux through SLC4A11: a route defective in genetic corneal diseases. Hum. Mol. Genet. 22, 4579–4590 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Lopez, I. A. et al. Slc4a11 gene disruption in mice: cellular targets of sensorineuronal abnormalities. J. Biol. Chem. 284, 26882–26896 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Desir, J. & Abramowicz, M. Congenital hereditary endothelial dystrophy with progressive sensorineural deafness (Harboyan syndrome). Orphanet J. Rare Dis. 3, 28 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Feder, R. S. et al. Subepithelial mucinous corneal dystrophy. Clinical and pathological correlations. Arch. Ophthalmol. 111, 1106–1114 (1993).

    Article  CAS  PubMed  Google Scholar 

  162. Pole, C. et al. High-resolution optical coherence tomography findings of Lisch epithelial corneal dystrophy. Cornea 35, 392–394 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Patel, D. V., Grupcheva, C. N. & McGhee, C. N. J. Imaging the microstructural abnormalities of Meesmann corneal dystrophy by in vivo confocal microscopy. Cornea 24, 669–673 (2005).

    Article  PubMed  Google Scholar 

  164. Klintworth, G. K. Corneal dystrophies. Orphanet J. Rare Dis. 4, 7 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Javadi, M.-A., Rezaei-Kanavi, M., Javadi, A. & Naghshgar, N. Meesmann corneal dystrophy; a clinico-pathologic, ultrastructural and confocal scan report. J. Ophthalmic Vis. Res. 5, 122–126 (2010).

    PubMed  PubMed Central  Google Scholar 

  166. Kurbanyan, K., Sejpal, K. D., Aldave, A. J. & Deng, S. X. In vivo confocal microscopic findings in Lisch corneal dystrophy. Cornea 31, 437 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Ide, T. et al. A spectrum of clinical manifestations of gelatinous drop-like corneal dystrophy in Japan. Am. J. Ophthalmol. 137, 1081–1084 (2004).

    Article  PubMed  Google Scholar 

  168. Kobayashi, A. & Sugiyama, K. In vivo laser confocal microscopy findings for Bowman’s layer dystrophies (Thiel-Behnke and Reis-Bücklers corneal dystrophies). Ophthalmology 114, 69–75 (2007).

    Article  PubMed  Google Scholar 

  169. Werner, L. P., Werner, L., Dighiero, P., Legeais, J. M. & Renard, G. Confocal microscopy in Bowman and stromal corneal dystrophies. Ophthalmology 106, 1697–1704 (1999).

    Article  CAS  PubMed  Google Scholar 

  170. Nowinska, A. K. et al. Comparative study of anterior eye segment measurements with spectral swept-source and time-domain optical coherence tomography in eyes with corneal dystrophies. Biomed. Res. Int. 2015, 805367 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Chaurasia, S., Ramappa, M. & Mishra, D. K. Clinical diversity in macular corneal dystrophy: an optical coherence tomography study. Int. Ophthalmol. 39, 2883–2888 (2019).

    Article  PubMed  Google Scholar 

  172. Rubinstein, Y. et al. Macular corneal dystrophy and posterior corneal abnormalities. Cornea 35, 1605–1610 (2016).

    Article  PubMed  Google Scholar 

  173. Sarosiak, A. et al. Clinical diversity in patients with Schnyder corneal dystrophy — a novel and known UBIAD1 pathogenic variants. Graefes Arch. Clin. Exp. Ophthalmol. 256, 2127–2134 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Lisch, W. et al. Schnyder’s dystrophy. Progression and metabolism. Ophthalmic Paediatr. Genet. 7, 45–56 (1986).

    Article  CAS  PubMed  Google Scholar 

  175. Weiss, J. S. et al. Genetic analysis of 14 families with Schnyder crystalline corneal dystrophy reveals clues to UBIAD1 protein function. Am. J. Med. Genet. A 146A, 271–283 (2008).

    Article  CAS  PubMed  Google Scholar 

  176. Lin, B. R. et al. Identification of the first de novo UBIAD1 gene mutation associated with Schnyder corneal dystrophy. J. Ophthalmol. 2016, 1968493 (2016).

    PubMed  PubMed Central  Google Scholar 

  177. Witschel, H., Fine, B. S., Grützner, P. & McTigue, J. W. Congenital hereditary stromal dystrophy of the cornea. Arch. Ophthalmol. 96, 1043–1051 (1978).

    Article  CAS  PubMed  Google Scholar 

  178. Jiao, X. et al. Genetic linkage of Francois-Neetens fleck (Mouchetée) corneal dystrophy to chromosome 2q35. Hum. Genet. 112, 593–599 (2003).

    Article  CAS  PubMed  Google Scholar 

  179. Akova, Y. A., Unlü, N. & Duman, S. Fleck dystrophy of the cornea; a report of cases from three generations of a family. Eur. J. Ophthalmol. 4, 123–125 (1994).

    Article  CAS  PubMed  Google Scholar 

  180. Moshegov, C. N., Hoe, W. K., Wiffen, S. J. & Daya, S. M. Posterior amorphous corneal dystrophy: a new pedigree with phenotypic variation. Ophthalmology 103, 474–478 (1996).

    Article  CAS  PubMed  Google Scholar 

  181. Kontadakis, G. A., Kymionis, G. D., Kankariya, V. P., Papadiamantis, A. G. & Pallikaris, A. I. Corneal confocal microscopy findings in sporadic cases of pre-Descemet corneal dystrophy. Eye Contact Lens 40, e8–e12 (2014).

    Article  PubMed  Google Scholar 

  182. Lagrou, L., Midgley, J. & Romanchuk, K. G. Punctiform and polychromatophilic dominant pre-Descemet corneal dystrophy. Cornea 35, 572–575 (2016).

    Article  PubMed  Google Scholar 

  183. Soh, Y. Q. & Mehta, J. S. Selective endothelial removal for Peters anomaly. Cornea 37, 382–385 (2018).

    Article  PubMed  Google Scholar 

  184. Acar, B. T., Bozkurt, K. T., Duman, E. & Acar, S. Bilateral cloudy cornea: is the usual suspect congenital hereditary endothelial dystrophy or stromal dystrophy? BMJ Case Rep. 2016, bcr2015214094 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  185. Yu Chan, J. Y., Choy, B. N., Ng, A. L. & Shum, J. W. Review on the management of primary congenital glaucoma. J. Curr. Glaucoma Pract. 9, 92–99 (2015).

    Article  PubMed  Google Scholar 

  186. Wacker, K., McLaren, J. W., Amin, S. R., Baratz, K. H. & Patel, S. V. Corneal high-order aberrations and backscatter in Fuchs’ endothelial corneal dystrophy. Ophthalmology 122, 1645–1652 (2015).

    Article  PubMed  Google Scholar 

  187. Fritz, M. et al. Diurnal variation in corneal edema in Fuchs endothelial corneal dystrophy. Am. J. Ophthalmol. 207, 351–355 (2019).

    Article  CAS  PubMed  Google Scholar 

  188. Read, S. A. & Collins, M. J. Diurnal variation of corneal shape and thickness. Optom. Vis. Sci. 86, 170–180 (2009).

    Article  PubMed  Google Scholar 

  189. Soliman, A. Z., Xing, C., Radwan, S. H., Gong, X. & Mootha, V. V. Correlation of severity of Fuchs endothelial corneal dystrophy with triplet repeat expansion in TCF4. JAMA Ophthalmol. 133, 1386–1391 (2015).

    Article  PubMed  Google Scholar 

  190. Eghrari, A. O. et al. CTG18.1 expansion in TCF4 increases likelihood of transplantation in Fuchs corneal dystrophy. Cornea 36, 40–43 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  191. Liskova, P., Filipec, M., Merjava, S., Jirsova, K. & Tuft, S. J. Variable ocular phenotypes of posterior polymorphous corneal dystrophy caused by mutations in the ZEB1 gene. Ophthalmic Genet. 31, 230–234 (2010).

    Article  CAS  PubMed  Google Scholar 

  192. Cibis, G. W., Krachmer, J. A., Phelps, C. D. & Weingeist, T. A. The clinical spectrum of posterior polymorphous dystrophy. Arch. Ophthalmol. 95, 1529–1537 (1977).

    Article  CAS  PubMed  Google Scholar 

  193. Lefebvre, V., Sowka, J. W. & Frauens, B. J. The clinical spectrum between posterior polymorphous dystrophy and iridocorneal endothelial syndromes. Optometry 80, 431–436 (2009).

    Article  PubMed  Google Scholar 

  194. Krachmer, J. H. Posterior polymorphous corneal dystrophy: a disease characterized by epithelial-like endothelial cells which influence management and prognosis. Trans. Am. Ophthalmol. Soc. 83, 413–475 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Liskova, P., Palos, M., Hardcastle, A. J. & Vincent, A. L. Further genetic and clinical insights of posterior polymorphous corneal dystrophy 3. JAMA Ophthalmol. 131, 1296–1303 (2013).

    Article  CAS  PubMed  Google Scholar 

  196. Ho, C. L. & Walton, D. S. Primary congenital glaucoma: 2004 update. J. Pediatr. Ophthalmol. Strabismus 41, 271–288 (2004).

    Article  PubMed  Google Scholar 

  197. Tan, Y.-L., Chua, J. & Ho, C.-L. Updates on the surgical management of pediatric glaucoma. Asia Pac. J. Ophthalmol. 5, 85–92 (2016).

    Article  Google Scholar 

  198. Singh, R. P. et al. Alcohol delamination of the corneal epithelium for recalcitrant recurrent corneal erosion syndrome: a prospective study of efficacy and safety. Br. J. Ophthalmol. 91, 908–911 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  199. Watson, S. L. & Leung, V. Interventions for recurrent corneal erosions. Cochrane Database Syst. Rev. 7, CD001861 (2018).

    PubMed  Google Scholar 

  200. Lee, W.-S., Lam, C. K. & Manche, E. E. Phototherapeutic keratectomy for epithelial basement membrane dystrophy. Clin. Ophthalmol. 11, 15–22 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  201. Jalbert, I. & Stapleton, F. Management of symptomatic Meesmann dystrophy. Optom. Vis. Sci. 86, E1202–E1206 (2009).

    Article  PubMed  Google Scholar 

  202. Bourne, W. M. Soft contact lens wear decreases epithelial microcysts in Meesmann’s corneal dystrophy. Trans. Am. Ophthalmol. Soc. 84, 170–182 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Zarei-Ghanavati, M. & Liu, C. Keratoprosthesis: current choices and future development. Asia Pac. J. Ophthalmol. 8, 429–431 (2019).

    Article  Google Scholar 

  204. Lekhanont, K., Jongkhajornpong, P., Chuephanich, P., Inatomi, T. & Kinoshita, S. Boston type 1 keratoprosthesis for gelatinous drop-like corneal dystrophy. Optom. Vis. Sci. 93, 640–646 (2016).

    Article  PubMed  Google Scholar 

  205. Avadhanam, V., Messina, M., Said, D. G. & Dua, H. S. Alcohol delamination of corneal epithelium in recurrent granular dystrophy. Ophthalmology 123, 2050–2052 (2016).

    Article  PubMed  Google Scholar 

  206. Seitz, B. & Lisch, W. Stage-related therapy of corneal dystrophies. Dev. Ophthalmol. 48, 116–153 (2011).

    Article  PubMed  Google Scholar 

  207. Dinh, R., Rapuano, C. J., Cohen, E. J. & Laibson, P. R. Recurrence of corneal dystrophy after excimer laser phototherapeutic keratectomy. Ophthalmology 106, 1490–1497 (1999).

    Article  CAS  PubMed  Google Scholar 

  208. Stewart, O. G., Pararajasegaram, P., Cazabon, J. & Morrell, A. J. Visual and symptomatic outcome of excimer phototherapeutic keratectomy (PTK) for corneal dystrophies. Eye 16, 126–131 (2002).

    Article  CAS  PubMed  Google Scholar 

  209. Reddy, J. C., Rapuano, C. J., Hammersmith, K. M. & Nagra, P. K. Clinical outcomes of surgical intervention for stromal corneal dystrophies. Invest. Ophthalmol. Vis. Sci. 53, 6052–6052 (2012).

    Google Scholar 

  210. Lewis, D. R., Price, M. O., Feng, M. T. & Price, F. W. Jr. Recurrence of granular corneal dystrophy type 1 after phototherapeutic keratectomy, lamellar keratoplasty, and penetrating keratoplasty in a single population. Cornea 36, 1227–1232 (2017).

    PubMed  Google Scholar 

  211. Marcon, A. S., Cohen, E. J., Rapuano, C. J. & Laibson, P. R. Recurrence of corneal stromal dystrophies after penetrating keratoplasty. Cornea 22, 19–21 (2003).

    Article  PubMed  Google Scholar 

  212. Küchle, M., Green, W. R., Völcker, H. E. & Barraquer, J. Reevaluation of corneal dystrophies of Bowman’s layer and the anterior stroma (Reis-Bücklers and Thiel-Behnke types): a light and electron microscopic study of eight corneas and a review of the literature. Cornea 14, 333–354 (1995).

    Article  PubMed  Google Scholar 

  213. Reddy, J. C. et al. Clinical outcomes and risk factors for graft failure after deep anterior lamellar keratoplasty and penetrating keratoplasty for macular corneal dystrophy. Cornea 34, 171–176 (2015).

    Article  PubMed  Google Scholar 

  214. Köksal, M., Kargi, S., Gürelik, G. & Akata, F. Phototherapeutic keratectomy in Schnyder crystalline corneal dystrophy. Cornea 23, 311–313 (2004).

    Article  PubMed  Google Scholar 

  215. Paparo, L. G. et al. Phototherapeutic keratectomy for Schnyder’s crystalline corneal dystrophy. Cornea 19, 343–347 (2000).

    Article  CAS  PubMed  Google Scholar 

  216. Freddo, T. F., Polack, F. M. & Leibowitz, H. M. Ultrastructural changes in the posterior layers of the cornea in Schnyder’s crystalline dystrophy. Cornea 8, 170–177 (1989).

    Article  CAS  PubMed  Google Scholar 

  217. Mehta, J. S. et al. Surgical management and genetic analysis of a Chinese family with the S171P mutation in the UBIAD1 gene, the gene for Schnyder corneal dystrophy. Br. J. Ophthalmol. 93, 926–931 (2009).

    Article  CAS  PubMed  Google Scholar 

  218. Zhu, A. Y., Marquezan, M. C., Kraus, C. L. & Prescott, C. R. Pediatric corneal transplants: review of current practice patterns. Cornea 37, 973–980 (2018).

    Article  PubMed  Google Scholar 

  219. Trief, D., Marquezan, M. C., Rapuano, C. J. & Prescott, C. R. Pediatric corneal transplants. Curr. Opin. Ophthalmol. 28, 477–484 (2017).

    Article  PubMed  Google Scholar 

  220. Eghrari, A. O. et al. Automated retroillumination photography analysis for objective assessment of Fuchs corneal dystrophy. Cornea 36, 44–47 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  221. AlArrayedh, H., Collum, L. & Murphy, C. C. Outcomes of penetrating keratoplasty in congenital hereditary endothelial dystrophy. Br. J. Ophthalmol. 102, 19–25 (2018).

    Article  PubMed  Google Scholar 

  222. Özdemir, B. et al. Penetrating keratoplasty in congenital hereditary endothelial dystrophy. Cornea 31, 359–365 (2012).

    Article  PubMed  Google Scholar 

  223. Schaumberg, D. A., Moyes, A. L., Gomes, J. A. & Dana, M. R. Corneal transplantation in young children with congenital hereditary endothelial dystrophy. Multicenter Pediatric Keratoplasty Study. Am. J. Ophthalmol. 127, 373–378 (1999).

    Article  CAS  PubMed  Google Scholar 

  224. Mohebbi, M., Nabavi, A., Fadakar, K. & Hashemi, H. Outcomes of Descemet-stripping automated endothelial keratoplasty in congenital hereditary endothelial dystrophy. Eye Contact Lens 46, 57–62 (2020).

    Article  PubMed  Google Scholar 

  225. Madi, S., Santorum, P. & Busin, M. Descemet stripping automated endothelial keratoplasty in pediatric age group. Saudi J. Ophthalmol. 26, 309–313 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  226. Ashar, J. N., Ramappa, M. & Vaddavalli, P. K. Paired-eye comparison of Descemet’s stripping endothelial keratoplasty and penetrating keratoplasty in children with congenital hereditary endothelial dystrophy. Br. J. Ophthalmol. 97, 1247–1249 (2013).

    Article  PubMed  Google Scholar 

  227. Ashar, J. N., Madhavi Latha, K. & Vaddavalli, P. K. Descemet’s stripping endothelial keratoplasty (DSEK) for children with congenital hereditary endothelial dystrophy: surgical challenges and 1-year outcomes. Graefes Arch. Clin. Exp. Ophthalmol. 250, 1341–1345 (2012).

    Article  PubMed  Google Scholar 

  228. Yang, F. et al. Descemet stripping endothelial keratoplasty in pediatric patients with congenital hereditary endothelial dystrophy. Am. J. Ophthalmol. 209, 132–140 (2020).

    Article  PubMed  Google Scholar 

  229. Anwar, H. M. & El-Danasoury, A. Endothelial keratoplasty in children. Curr. Opin. Ophthalmol. 25, 340–346 (2014).

    Article  PubMed  Google Scholar 

  230. Quantock, A. J., Nishida, K. & Kinoshita, S. Histopathology of recurrent gelatinous drop-like corneal dystrophy. Cornea 17, 215–221 (1998).

    Article  CAS  PubMed  Google Scholar 

  231. Ang, M., Soh, Y., Htoon, H. M., Mehta, J. S. & Tan, D. Five-year graft survival comparing Descemet stripping automated endothelial keratoplasty and penetrating keratoplasty. Ophthalmology 123, 1646–1652 (2016).

    Article  PubMed  Google Scholar 

  232. Venkatraman, A. et al. Effect of osmolytes on in-vitro aggregation properties of peptides derived from TGFBIp. Sci. Rep. 10, 4011 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Courtney, D. G. et al. Development of allele-specific gene-silencing siRNAs for TGFBI Arg124Cys in lattice corneal dystrophy type I. Invest. Ophthalmol. Vis. Sci. 55, 977–985 (2014).

    Article  CAS  PubMed  Google Scholar 

  234. Yuan, C., Zins, E. J., Clark, A. F. & Huang, A. J. W. Suppression of keratoepithelin and myocilin by small interfering RNAs (siRNA) in vitro. Mol. Vis. 13, 2083–2095 (2007).

    CAS  PubMed  Google Scholar 

  235. Christie, K. A. et al. Towards personalised allele-specific CRISPR gene editing to treat autosomal dominant disorders. Sci. Rep. 7, 16174 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  236. Kim, E. K., Kim, S. & Maeng, Y.-S. Generation of TGFBI knockout ABCG2+/ABCB5+ double-positive limbal epithelial stem cells by CRISPR/Cas9-mediated genome editing. PLoS One 14, e0211864 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Courtney, D. G. et al. siRNA silencing of the mutant keratin 12 allele in corneal limbal epithelial cells grown from patients with Meesmann’s epithelial corneal dystrophy. Invest. Ophthalmol. Vis. Sci. 55, 3352–3360 (2014).

    Article  CAS  PubMed  Google Scholar 

  238. Liao, H. et al. Development of allele-specific therapeutic siRNA in Meesmann epithelial corneal dystrophy. PLoS One 6, e28582 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Szabó, D. J. et al. Ex vivo 3D human corneal stroma model for Schnyder corneal dystrophy - role of autophagy in its pathogenesis and resolution. Histol. Histopathol. 33, 455–462 (2018).

    PubMed  Google Scholar 

  240. Peh, G. S. L. et al. Propagation of human corneal endothelial cells: a novel dual media approach. Cell Transpl. 24, 287–304 (2015). One of the first published methods to reliably culture human corneal endothelial cells at significant scale while minimizing the loss of endothelial cell properties during culture.

    Article  Google Scholar 

  241. Peh, G. S. L., Beuerman, R. W., Colman, A., Tan, D. T. & Mehta, J. S. Human corneal endothelial cell expansion for corneal endothelium transplantation: an overview. Transplantation 91, 811–819 (2011).

    Article  PubMed  Google Scholar 

  242. Wahlig, S., Kocaba, V. & Mehta, J. S. Cultured cells and ROCK inhibitor for bullous keratopathy. N. Engl. J. Med. 379, 1184 (2018).

    Article  PubMed  Google Scholar 

  243. Zarouchlioti, C. et al. Antisense therapy for a common corneal dystrophy ameliorates TCF4 repeat expansion-mediated toxicity. Am. J. Hum. Genet. 102, 528–539 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Jinek, M. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816–821 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Feng, Z. et al. Efficient genome editing in plants using a CRISPR/Cas system. Cell Res. 23, 1229–1232 (2013). This article and that of Jinek et al. are pioneering publications describing the potential use of the CRISPR–Cas9 platform for human gene therapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank W. Y. Ng, F. L. Lian, V. Phua and K. Sandhanam from the Singapore National Eye Centre for their help in obtaining the clinical images used in this article.

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Authors and Affiliations

  1. Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore, Singapore

    Yu Qiang Soh, Viridiana Kocaba & Jodhbir S. Mehta

  2. Singapore National Eye Centre, Singapore, Singapore

    Yu Qiang Soh & Jodhbir S. Mehta

  3. Ophthalmology Academic Clinical Program, Duke-NUS Graduate Medical School, Singapore, Singapore

    Yu Qiang Soh & Jodhbir S. Mehta

  4. Department of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore, Singapore

    Yu Qiang Soh & Jodhbir S. Mehta

  5. Netherlands Institute for Innovative Ocular Surgery, Rotterdam, Netherlands

    Viridiana Kocaba

  6. Department of Ophthalmology, Pathology and Pharmacology, Louisiana State University, School of Medicine, New Orleans, USA

    Jayne S. Weiss

  7. Cornea and Refractive Surgery Service, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA

    Ula V. Jurkunas

  8. Schepens Eye Research Institute, Boston, Massachusetts, USA

    Ula V. Jurkunas

  9. Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA

    Ula V. Jurkunas

  10. Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Shigeru Kinoshita

  11. Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, USA

    Anthony J. Aldave

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  1. Yu Qiang Soh
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  2. Viridiana Kocaba
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  7. Jodhbir S. Mehta
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Contributions

All authors contributed to all sections of the Primer, with J.S.M. coordinating the project.

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Correspondence to Jodhbir S. Mehta.

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Nature Reviews Disease Primers thanks C. Rapuano, S. Tuft and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Soh, Y.Q., Kocaba, V., Weiss, J.S. et al. Corneal dystrophies. Nat Rev Dis Primers 6, 46 (2020). https://doi.org/10.1038/s41572-020-0178-9

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