We describe the search for mutations in six unrelated Czech and four unrelated British families with posterior polymorphous corneal dystrophy (PPCD); a relatively rare eye disorder. Coding exons and intron/exon boundaries of all three genes (VSX1, COL8A2, and ZEB1/TCF8) previously reported to be implicated in the pathogenesis of this disorder were screened by DNA sequencing. Four novel pathogenic mutations were identified in four families; two deletions, one nonsense, and one duplication within exon 7 in the ZEB1 gene located at 10p11.2. We also genotyped the Czech patients to test for a founder haplotype and lack of disease segregation with the 20p11.2 locus we previously described. Although a systematic clinical examination was not performed, our investigation does not support an association between ZEB1 changes and self reported non-ocular anomalies. In the remaining six families no disease causing mutations were identified thereby indicating that as yet unidentified gene(s) are likely to be responsible for PPCD.

Division of Molecular Genetics Institute of Ophthalmology UCL London United Kingdom

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Aldave AJ, Yellore VS, Principe AH, Abedi G, Merrill K, Raber I, Small KW, Udar N. Candidate Gene Screening for Posterior Polymorphous Dystrophy. Invest. Ophthalmol. Vis. Sci. 2004;45(5):1526.

Antonarakis SE, Nomenclature Working Group Recommendations for a nomenclature system for human gene mutations. Hum Mutat. 1998;11(1):1–3. PubMed

Biswas S, Munier FL, Yardley J, Hart-Holden N, Perveen R, Cousin P, Sutphin JE, Noble B, Batterbury M, Kielty C. Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy. Hum Mol Genet. 2001;10(21):2415–23. others. PubMed

Cibis GW, Krachmer JA, Phelps CD, Weingeist TA. The clinical spectrum of posterior polymorphous dystrophy. Arch Ophthalmol. 1977;95(9):1529–37. PubMed

de Felice GP, Braidotti P, Viale G, Bergamini F, Vinciguerra P. Posterior polymorphous dystrophy of the cornea. An ultrastructural study. Graefes Arch Clin Exp Ophthalmol. 1985;223(5):265–71. PubMed

den Dunnen JT, Antonarakis SE. Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat. 2000;15(1):7–12. PubMed

Gwilliam R, Liskova P, Filipec M, Kmoch S, Jirsova K, Huckle EJ, Stables CL, Bhattacharya SS, Hardcastle AJ, Deloukas P. Posterior polymorphous corneal dystrophy in Czech families maps to chromosome 20 and excludes the VSX1 gene. Invest Ophthalmol Vis Sci. 2005;46(12):4480–4. others. PubMed

Henriquez AS, Kenyon KR, Dohlman CH, Boruchoff SA, Forstot SL, Meyer RF, Hanninen LA. Morphologic characteristics of posterior polymorphous dystrophy. A study of nine corneas and review of the literature. Surv Ophthalmol. 1984;29(2):139–47. PubMed

Heon E, Greenberg A, Kopp KK, Rootman D, Vincent AL, Billingsley G, Priston M, Dorval KM, Chow RL, McInnes RR. VSX1: A gene for posterior polymorphous dystrophy and keratoconus. Hum. Mol. Genet. 2002;11(9):1029–1036. others. PubMed

Heon E, Mathers WD, Alward WL, Weisenthal RW, Sunden SL, Fishbaugh JA, Taylor CM, Krachmer JH, Sheffield VC, Stone EM. Linkage of posterior polymorphous corneal dystrophy to 20q11. Hum Mol Genet. 1995;4(3):485–8. PubMed

Ikeda K, Halle JP, Stelzer G, Meisterernst M, Kawakami K. Involvement of negative cofactor NC2 in active repression by zinc finger-homeodomain transcription factor AREB6. Mol Cell Biol. 1998;18(1):10–8. PubMed PMC

Krachmer JH. Posterior polymorphous corneal dystrophy: a disease characterized by epithelial-like endothelial cells which influence management and prognosis. Trans Am Ophthalmol Soc. 1985;83:413–75. PubMed PMC

Krafchak CM, Pawar H, Moroi SE, Sugar A, Lichter PR, Mackey DA, Mian S, Nairus T, Elner V, Schteingart MT. Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells. Am J Hum Genet. 2005;77(5):694–708. others. PubMed PMC

Laganowski HC, Sherrard ES, Muir MG. The posterior corneal surface in posterior polymorphous dystrophy: a specular microscopical study. Cornea. 1991;10(3):224–32. PubMed

Polack FM, Bourne WM, Forstot SL, Yamaguchi T. Scanning electron microscopy of posterior polymorphous corneal dystrophy. Am J Ophthalmol. 1980;89(4):575–84. PubMed

Soukup F. Polymorphous Posterior Degeneration of the Cornea. Cesk Oftalmol. 1964;20:181–6. PubMed

Tripathi RC, Casey TA, Wise G. Hereditary posterior polymorphous dystrophy an ultrastructural and clinical report. Trans Ophthal Soc U.K. 1974;94:211–25.

Valleix S, Nedelec B, Rigaudiere F, Dighiero P, Pouliquen Y, Renard G, Le Gargasson JF, Delpech M. H244R VSX1 is associated with selective cone ON bipolar cell dysfunction and macular degeneration in a PPCD family. Invest Ophthalmol Vis Sci. 2006;47(1):48–54. PubMed

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Heterozygous deletions at the ZEB1 locus verify haploinsufficiency as the mechanism of disease for posterior polymorphous corneal dystrophy type 3

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