Abstract
Purpose
To describe a severe phenotype of Meesmann’s epithelial corneal dystrophy (MECD) and to determine the underlying molecular cause.
Methods
We identified a 30-member family affected by MECD and examined 11 of the 14 affected individuals. Excised corneal tissue from one affected individual was examined histologically. We used PCR and direct sequencing to identify mutation of the coding regions of the KRT3 and KRT12 genes.
Results
Cases had an unusually severe phenotype with large numbers of intraepithelial cysts present from infancy and they developed subepithelial fibrosis in the second to third decade. In some individuals, the cornea became superficially vascularized, a change accompanied by the loss of clinically obvious epithelial cysts. Visual loss from amblyopia or corneal opacity was common and four individuals were visually impaired (≤6/24 bilaterally) and one was blind (<6/60 bilaterally). In all affected family members, there was a heterozygous missense mutation c. 395T>C (p. L132P) in exon 1 of the KRT12 gene, which codes for the helix-initiation motif of the K12 polypeptide. This sequence change was not found in unaffected family members or in 100 unaffected controls.
Conclusions
The Leu132Pro missense mutation is within the helix-initiation motif of the keratin and is predicted to result in a significant structural change of the K12 protein. The clinical effects are markedly more severe than the phenotype usually associated with the Arg135Thr mutation within this motif, most frequently seen in European patients with MECD.
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References
Meesmann A . über eine bisher nicht beschriebene, dominant vererbte Dystrophia epithelialis corneae. Ber Zusammenkunft Dtsch Ophthalmol Ges 1938; 52: 154–158.
Meesmann A, Wilke F . Klinsche und anatomische Untersuchungen uber eine bisher unbekannte, dominant verebre Epitjeldystrophie der Hornhaut. Klin Monbl Augenheilkd 1939; 103: 361–391.
Ehlers N, Hjortdal J, Nielsen K, Thiel HJ, Orntoft T . Phenotypic variability in Meesmann's dystrophy: clinical review of the literature and presentation of a family genetically identical to the original family. Acta Ophthalmol 2008; 86 (1): 40–44.
Sullivan LS, Baylin EB, Font R, Daiger SP, Pepose JS, Clinch TE et al. A novel mutation of the Keratin 12 gene responsible for a severe phenotype of Meesmann's corneal dystrophy. Mol Vis 2007; 13: 975–980.
Fine BS, Yanoff M, Pitts E, Slaughter FD . Meesmann's epithelial dystrophy of the cornea. Am J Ophthalmol 1977; 83 (5): 633–642.
Tremblay M, Dube I . Meesmann’s corneal dystrophy: ultrastructural features. Can J Ophthalmol 1982; 17 (1): 24–28.
Irvine AD, Corden LD, Swensson O, Swensson B, Moore JE, Frazer DG et al. Mutations in cornea-specific keratin K3 or K12 genes cause Meesmann's corneal dystrophy. Nat Genet 1997; 16 (2): 184–187.
Omary MB, Coulombe PA, McLean WH . Intermediate filament proteins and their associated diseases. N Engl J Med 2004; 351 (20): 2087–2100.
http://www.interfil.org/index.php. The Human Intermediate Filament Database http://www.interfil.org/index.php. Updated 6 June 2011. Accessed 11 June 2011. D [H]. G. Accessed 10 June 2011.
Chamcheu JC, Siddiqui IA, Syed DN, Adhami VM, Liovic M, Mukhtar H . Keratin gene mutations in disorders of human skin and its appendages. Arch Biochem Biophys 2011; 508 (2): 123–137.
Kao WW, Liu CY, Converse RL, Shiraishi A, Kao CW, Ishizaki M et al. Keratin 12-deficient mice have fragile corneal epithelia. Invest Ophthalmol Vis Sci 1996; 37 (13): 2572–2584.
Szeverenyi I, Cassidy AJ, Chung CW, Lee BT, Common JE, Ogg SC et al. The Human Intermediate Filament Database: comprehensive information on a gene family involved in many human diseases. Hum Mutat 2008; 29 (3): 351–360.
Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, DeBenedetto A et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 2009; 124 (3 Suppl 2): R7–R12.
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: 133–144.
Chiou AG, Florakis GJ, Copeland RL, Williams VA, McCormick SA, Chiesa R . Recurrent Meesmann’s corneal epithelial dystrophy after penetrating keratoplasty. Cornea 1998; 17 (5): 566–570.
Liao H, Irvine AD, Macewen CJ, Weed KH, Porter L, Corden LD et al. Development of allele-specific therapeutic siRNA in Meesmann epithelial corneal dystrophy. PLoS One 2011; 6 (12): e28582.
Wang LJ, Tian X, Zhang QS, Liu L . [Analysis of mutation in KRT12 gene in a Chinese family with Meesmann's corneal dystrophy]. Zhonghua Yan Ke Za Zhi 2007; 43 (10): 885–889.
Hatzfeld M, Weber K . The coiled coil of in vitro assembled keratin filaments is a heterodimer of type I and II keratins: use of site-specific mutagenesis and recombinant protein expression. J Cell Biol 1990; 110 (4): 1199–1210.
Liu CY, Zhu G, Westerhausen-Larson A, Converse R, Kao CW, Sun TT et al. Cornea-specific expression of K12 keratin during mouse development. Curr Eye Res 1993; 12 (11): 963–974.
Lu X, Lane EB . Retrovirus-mediated transgenic keratin expression in cultured fibroblasts: specific domain functions in keratin stabilization and filament formation. Cell 1990; 62 (4): 681–696.
Moll R, Franke WW, Schiller DL, Geiger B, Krepler R . The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell 1982; 31 (1): 11–24.
Corden LD, McLean WH . Human keratin diseases: hereditary fragility of specific epithelial tissues. Exp Dermatol 1996; 5 (6): 297–307.
Lane EB . Keratin diseases. Curr Opin Genet Dev 1994; 4 (3): 412–418.
Ishida-Yamamoto A, McGrath JA, Chapman SJ, Leigh IM, Lane EB, Eady RA . Epidermolysis bullosa simplex (Dowling-Meara type) is a genetic disease characterized by an abnormal keratin-filament network involving keratins K5 and K14. J Invest Dermatol 1991; 97 (6): 959–968.
Coulombe PA, Hutton ME, Letai A, Hebert A, Paller AS, Fuchs E . Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and functional analyses. Cell 1991; 66 (6): 1301–1311.
Chaloin-Dufau C, Sun TT, Dhouailly D . Appearance of the keratin pair K3/K12 during embryonic and adult corneal epithelial differentiation in the chick and in the rabbit. Cell Differ Dev 1990; 32 (2): 97–108.
Nishida K, Honma Y, Dota A, Kawasaki S, Adachi W, Nakamura T et al. Isolation and chromosomal localization of a cornea-specific human keratin 12 gene and detection of four mutations in Meesmann corneal epithelial dystrophy. Am J Hum Genet 1997; 61 (6): 1268–1275.
Corden LD, Swensson O, Swensson B, Smith FJ, Rochels R, Uitto J et al. Molecular genetics of Meesmann's corneal dystrophy: ancestral and novel mutations in keratin 12 (K12) and complete sequence of the human KRT12 gene. Exp Eye Res 2000; 70 (1): 41–49.
Irvine AD, Coleman CM, Moore JE, Swensson O, Morgan SJ, McCarthy JH et al. A novel mutation in KRT12 associated with Meesmann’s epithelial corneal dystrophy. Br J Ophthalmol 2002; 86 (7): 729–732.
Acknowledgements
This research was funded by the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology (BMRC 089) and by Moorfields Eye Hospital Special Trustees.
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Hassan, H., Thaung, C., Ebenezer, N. et al. Severe Meesmann’s epithelial corneal dystrophy phenotype due to a missense mutation in the helix-initiation motif of keratin 12. Eye 27, 367–373 (2013). https://doi.org/10.1038/eye.2012.261
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DOI: https://doi.org/10.1038/eye.2012.261
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