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Kerato-epithelin mutations in four 5q31-linked corneal dystrophies

Abstract

Granular dystrophy Groenouw type I (CDGG1), Reis-Bücklers (CDRB), lattice type I (CDL1) and Avellino (ACD) are four 5q31-linked human autosomal dominant corneal dystrophies. Clinically, they show progressive opacification of the cornea leading to severe visual handicap. The nature of the deposits remains unknown in spite of amyloid aetiology ascribed to the last two. We generated a YAC contig of the linked region and, following cDNA selection, recovered the βig-h3 gene. In six affected families we identified missense mutations. All detected mutations occurred at the CpG dinucleotide of two arginine codons: R555W in one CDGG1, R555Q in one CDRB, R124C in two CDL1 and R124H in two ACD families. This suggests, as the last two diseases are characterized by amyloid deposits, that R124 mutated kerato-epithelin (the product of βig-h3) forms amyloidogenic intermediates that precipitate in the cornea. Our data establish a common molecular origin for the 5q31-linked corneal dystrophies.

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References

  1. Møller, H.U. Inter-familial variability and intra-familial similarities of granular corneal dystrophy Groenouw type I with respect to biomicroscopical appearance and symptomatology. Acta Ophthalmol. 67, 669–677 (1989).

    Article  Google Scholar 

  2. Klintworth, G.K. Lattice corneal dystrophy: an inherited variety of amyloidosis restricted to the cornea. Am. J. Pathol. 50, 371–399 (1967).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Folberg, R. et al. Clinically atypical granular corneal dystrophy with pathologic features of lattice-like amyloid deposits. Ophthalmology 95, 46–51 (1988).

    Article  CAS  Google Scholar 

  4. Rosenwasser, G.O. et al. Phenotypic variation in combined granular-lattice (Avellino) corneal dystrophy. Arch. Ophthalmol. 111, 1546–1552 (1993).

    Article  CAS  Google Scholar 

  5. Küchle, M. et al. 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  Google Scholar 

  6. Møller, H.U. Granular corneal dystrophy Groenouw type I (Grl) and Reis-Bücklers' corneal dystrophy (R-B) — one entity? Acta Ophthalmol. 67, 678–684 (1989).

    Article  Google Scholar 

  7. Eiberg, H. Møller, H.U. Berendt, I. & Mohr, J. Assignment of granular corneal dystrophy Groenouw type I locus to within a 2 cM interval. Eur. J. Hum. Genet. 2, 132–138 (1995).

    Article  Google Scholar 

  8. Stone, E.M. et al. Three autosomal dominant corneal dystrophies map to chromosome 5q. Nature Genet. 6, 47–51 (1994).

    Article  CAS  Google Scholar 

  9. Gregory, C.Y. Evans, K. & Bhattacharya, S.S. Genetic refinement of the chromosome 5q lattice corneal dystrophy to within a 2 cM interval. J. Med. Genet. 32, 224–226 (1995).

    Article  CAS  Google Scholar 

  10. Small, K.W. et al. Mapping of Reis-Bucklers' corneal dystrophy to chromosome 5q. Am. J. Ophthalmol. 121, 384–390 (1996).

    Article  CAS  Google Scholar 

  11. Korvatska, E. et al. Delineation of a 1-cM region on distal 5q containing the locus for corneal dystrophies Groenouw type I and lattice type I and exclusion of the candidate genes SPARC and LOX. Eur. J. Hum. Genet. 4, 214–218 (1996).

    Article  CAS  Google Scholar 

  12. Derry, J.M. Ochs, H.D. & Francke, U. Isolation of a novel gene mutated in Wiskott-Aldrich syndrome. Cell 78, 635–644 (1994).

    Article  CAS  Google Scholar 

  13. 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  Google Scholar 

  14. Skonier, J. et al. βig-h3: a transforming growth factor — responsive gene encoding a secreted protein that inhibits cell attachment in vitro and suppresses the growth of CHO cells in nude mice. DNA Cell Biol. 13, 571–584 (1994).

    Article  CAS  Google Scholar 

  15. Escribano, J. Hernando, N. Ghosh, S. Crabb, J. & Coca-Prados, M. cDNA from human ocular ciliary epithelium homologous to βig-h3 is preferentially expressed as an extracellular protein in the corneal epithelium. J. Cell. Physiol. 160, 511–521 (1994).

    Article  CAS  Google Scholar 

  16. Ruoslahti, E. Proteoglycans in cell regulation. J. Biol. Chem. 264, 13369–13372 (1989).

    CAS  PubMed  Google Scholar 

  17. Zinn, K. McAllister, L. & Goodman, C.S. Sequence analysis and neuronal expression of fasciclin I in grasshopper and Drosophila. Cell 53, 577–587 (1988).

    Article  CAS  Google Scholar 

  18. Takeshita, S. Kikuno, R. Tezuka, K. & Amann, E. Osteoblast-specific factor 2: cloning of a putative bone adhesion protein with homology with the insect protein fasciclin I. Biochem. J. 294, 271–278 (1993).

    Article  CAS  Google Scholar 

  19. Lupas, A. Van Dyke, M. & Stock, J. Predicting coiled coils from protein sequences. Science 252, 1162–1164 (1991).

    Article  CAS  Google Scholar 

  20. Blake, D.J. et al. Coiled-coil regions in the carboxy-terminal domains of dystrophin and related proteins: potentials for protein–protein interaction. Trends Biochem. Sci. 20, 133–135 (1995).

    Article  CAS  Google Scholar 

  21. Sipe, J.D. Amyloidosis. Crit. Rev. Clin. Lab. Sci. 31, 325–354 (1994).

    Article  CAS  Google Scholar 

  22. Gallo, G. Picken, M. Fangione, B. & Buxbaum, J. Nonamyloidotic monoclonal immunoglobulin deposits lack amyloid P-component. Modern Pathol. 1, 453–456 (1988).

    CAS  Google Scholar 

  23. Folberg, R. Stone, E.M. Sheffield, V.C. & Mathers, W.D. The relationship between granular, lattice type 1, and Avellino corneal dystrophies. Arch. Ophthalmol. 112, 1080–1085 (1994).

    Article  CAS  Google Scholar 

  24. Mannis, M.J. Krachmer, J.H. Rodrigues, M.M. & Pardos, G.J. Polymorphic amyloid degeneration of the cornea: a clinical and histopathologic study. Arch. Ophthalmol. 99, 1217–1223 (1981).

    Article  CAS  Google Scholar 

  25. Stock, E.L. Feder, R.S. O'Grady, R.B. Sguar, J. & Roth, S.I. Lattice corneal dystrophy type IIIa. Arch. Ophthalmol. 109, 354–358 (1991).

    Article  CAS  Google Scholar 

  26. Büchi, E.R. Daicker, B. Uffer, S. & Gudat, F. Primary gelatinous drop-like corneal dystrophy in a white woman. Cornea 13, 190–194 (1994).

    Article  Google Scholar 

  27. Altschul, S.F. et al. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 (1990).

    Article  CAS  Google Scholar 

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Munier, F., Korvatska, E., Djemaï, A. et al. Kerato-epithelin mutations in four 5q31-linked corneal dystrophies. Nat Genet 15, 247–251 (1997). https://doi.org/10.1038/ng0397-247

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