Biopolym. Cell. 2008; 24(1):60-68.
Molecular Biomedicine
Study of TGFBI gene mutations in Ukrainian patients with corneal dystrophies
1Pampukha V. M., 2Drozhyna G. I., 1Livshits L. A.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680
  2. Filatov Institute of eye diseases and tissue therapy, NAMS of Ukraine
    49/51, Boulevard Francais, Odessa, Ukraine, 65061


In our study Arg124Cys (exon 4), Thr538Arg, Ala546Thr, Arg555Thr, Arg55Gln (exon 12), His626Arg (exon 14) mutations of the TGFBI gene were analyzed using polymerase chain reaction followed by restriction digestion in 91 patients with different forms of corneal dystrophy and 31 clinically healthy individuals from 49 unrelated families. Our results show that TGFBI gene mutations analysis is important for differential diagnostics of corneal dystrophies with prognostic and therapeutic implications as well as for genetic consulting in high risk families.
Keywords: TGFBI gene, keratoepithelin, corneal dystrophy


[1] Skonier J, Neubauer M, Madisen L, Bennett K, Plowman GD, Purchio AF. cDNA cloning and sequence analysis of beta ig-h3, a novel gene induced in a human adenocarcinoma cell line after treatment with transforming growth factor-beta. DNA Cell Biol. 1992;11(7):511-22.
[2] Escribano J, Hernando N, Ghosh S, Crabb J, Coca-Prados M. cDNA from human ocular ciliary epithelium homologous to beta ig-h3 is preferentially expressed as an extracellular protein in the corneal epithelium. J Cell Physiol. 1994;160(3):511-21.
[3] Klintworth G. K., Enghild J. J., Valnickova Z. Discovery of a novel protein (beta ig-H3) in normal human cornea. Invest. Ophthalmol. Vis. Sci. 1994. 35 (Suppl):1938.
[4] Stone EM, Mathers WD, Rosenwasser GO, Holland EJ, Folberg R, Krachmer JH, Nichols BE, Gorevic PD, Taylor CM, Streb LM, et al. Three autosomal dominant corneal dystrophies map to chromosome 5q. Nat Genet. 1994;6(1):47-51.
[5] Munier FL, Korvatska E, Djema? A, Le Paslier D, Zografos L, Pescia G, Schorderet DF. Kerato-epithelin mutations in four 5q31-linked corneal dystrophies. Nat Genet. 1997;15(3):247-51.
[6] LeBaron RG, Bezverkov KI, Zimber MP, Pavelec R, Skonier J, Purchio AF. Beta IG-H3, a novel secretory protein inducible by transforming growth factor-beta, is present in normal skin and promotes the adhesion and spreading of dermal fibroblasts in vitro. J Invest Dermatol. 1995;104(5):844-9.
[7] Kim JE, Kim SJ, Lee BH, Park RW, Kim KS, Kim IS. Identification of motifs for cell adhesion within the repeated domains of transforming growth factor-beta-induced gene, betaig-h3. J Biol Chem. 2000;275(40):30907-15.
[8] Arnaout MA, Goodman SL, Xiong JP. Coming to grips with integrin binding to ligands. Curr Opin Cell Biol. 2002;14(5):641-51.
[9] Hashimoto K, Noshiro M, Ohno S, Kawamoto T, Satakeda H, Akagawa Y, Nakashima K, Okimura A, Ishida H, Okamoto T, Pan H, Shen M, Yan W, Kato Y. Characterization of a cartilage-derived 66-kDa protein (RGD-CAP/beta ig-h3) that binds to collagen. Biochim Biophys Acta. 1997;1355(3):303-14.
[10] Hanssen E, Reinboth B, Gibson MA. Covalent and non-covalent interactions of betaig-h3 with collagen VI. Beta ig-h3 is covalently attached to the amino-terminal region of collagen VI in tissue microfibrils. J Biol Chem. 2003;278(27):24334-41.
[11] Billings PC, Whitbeck JC, Adams CS, Abrams WR, Cohen AJ, Engelsberg BN, Howard PS, Rosenbloom J. The transforming growth factor-beta-inducible matrix protein (beta)ig-h3 interacts with fibronectin. J Biol Chem. 2002;277(31):28003-9.
[12] Zinn K, McAllister L, Goodman CS. Sequence analysis and neuronal expression of fasciclin I in grasshopper and Drosophila. Cell. 1988;53(4):577-87.
[13] Clout NJ, Hohenester E. A model of FAS1 domain 4 of the corneal protein beta(ig)-h3 gives a clearer view on corneal dystrophies. Mol Vis. 2003;9:440-8.
[14] Waring GO, Rodrigues MM, Laibson PR. Corneal dystrophies. I. Dystrophies of the epithelium, Bowman's layer and stroma. Surv Ophthalmol. 1978; 23(2):71-122.
[15] Jones M., Zimmerman L. Histopathologic differentiation of granular, Macular and lattice Dystrophies of the cornea. Am J Ophthalmol. 1961;51:394-410.
[16] Dighiero P, Niel F, Ellies P, D'Hermies F, Savoldelli M, Renard G, Delpech M, Valleix S. Histologic phenotype-genotype correlation of corneal dystrophies associated with eight distinct mutations in the TGFBI gene. Ophthalmology. 2001;108(4):818-23.
[17] Mashima Y, Nakamura Y, Noda K, Konishi M, Yamada M, Kudoh J, Shimizu N. A novel mutation at codon 124 (R124L) in the BIGH3 gene is associated with a superficial variant of granular corneal dystrophy. Arch Ophthalmol. 1999;117(1):90-3.
[18] Pampukha VM, Drozhyna GI, Livshits LA. TGFBI gene mutation analysis in families with hereditary corneal dystrophies from Ukraine. Ophthalmologica. 2004;218(6):411-4.
[19] Okada M, Yamamoto S, Watanabe H, Inoue Y, Tsujikawa M, Maeda N, Shimomura Y, Nishida K, Kinoshita S, Tano Y. Granular corneal dystrophy with homozygous mutations in the kerato-epithelin gene. Am J Ophthalmol. 1998;126(2):169-76.
[20] Mashima Y, Konishi M, Nakamura Y, Imamura Y, Yamada M, Ogata T, Kudoh J, Shimizu N. Severe form of juvenile corneal stromal dystrophy with homozygous R124H mutation in the keratoepithelin gene in five Japanese patients. Br J Ophthalmol. 1998;82(11):1280-4.
[21] Kanai A, Tanaka M, Kaneko H, Niwa Y, Nakajima A. Clinical and histopathological studies of the lattice dystrophy of the cornea. Nihon Ganka Gakkai Zasshi. 1973;77(4):357-67.
[22] Dubord PJ, Krachmer JH. Diagnosis of early lattice corneal dystrophy. Arch Ophthalmol. 1982;100(5):788-90.
[23] Maychuk YU. F., Orlovskaya L. Ye. Stromal dystrophy - clinical forms and treatment. Oftalmol Zh. 1993; 4:224–232.
[24] Endo S, Nguyen TH, Fujiki K, Hotta Y, Nakayasu K, Yamaguchi T, Ishida N, Kanai A. Leu518Pro mutation of the beta ig-h3 gene causes lattice corneal dystrophy type I. Am J Ophthalmol. 1999;128(1):104-6.
[25] Warren JF, Abbott RL, Yoon MK, Crawford JB, Spencer WH, Margolis TP. A new mutation (Leu569Arg) within exon 13 of the TGFBI (BIGH3) gene causes lattice corneal dystrophy type I. Am J Ophthalmol. 2003;136(5):872-8.
[26] Chakravarthi SV, Kannabiran C, Sridhar MS, Vemuganti GK. TGFBI gene mutations causing lattice and granular corneal dystrophies in Indian patients. Invest Ophthalmol Vis Sci. 2005;46(1):121-5.
[27] Stock EL, Feder RS, O'Grady RB, Sugar J, Roth SI. Lattice corneal dystrophy type IIIA. Clinical and histopathologic correlations. Arch Ophthalmol. 1991;109(3):354-8.
[28] Yamamoto S, Okada M, Tsujikawa M, Shimomura Y, Nishida K, Inoue Y, Watanabe H, Maeda N, Kurahashi H, Kinoshita S, Nakamura Y, Tano Y. A kerato-epithelin (betaig-h3) mutation in lattice corneal dystrophy type IIIA. Am J Hum Genet. 1998;62(3):719-22.
[29] Dighiero P, Drunat S, Ellies P, D'Hermies F, Savoldelli M, Legeais JM, Renard G, Delpech M, Grateau G, Valleix S. A new mutation (A546T) of the betaig-h3 gene responsible for a French lattice corneal dystrophy type IIIA. Am J Ophthalmol. 2000;129(2):248-51.
[30] Munier FL, Frueh BE, Othenin-Girard P, Uffer S, Cousin P, Wang MX, H?on E, Black GC, Blasi MA, Balestrazzi E, Lorenz B, Escoto R, Barraquer R, Hoeltzenbein M, Gloor B, Fossarello M, Singh AD, Arsenijevic Y, Zografos L, Schorderet DF. BIGH3 mutation spectrum in corneal dystrophies. Invest Ophthalmol Vis Sci. 2002;43(4):949-54.
[31] Stewart H, Black GC, Donnai D, Bonshek RE, McCarthy J, Morgan S, Dixon MJ, Ridgway AA. A mutation within exon 14 of the TGFBI (BIGH3) gene on chromosome 5q31 causes an asymmetric, late-onset form of lattice corneal dystrophy. Ophthalmology. 1999;106(5):964-70.
[32] Schmitt-Bernard CF, Guittard C, Arnaud B, Demaille J, Argiles A, Claustres M, Tuffery-Giraud S. BIGH3 exon 14 mutations lead to intermediate type I/IIIA of lattice corneal dystrophies. Invest Ophthalmol Vis Sci. 2000;41(6):1302-8.
[33] Fujiki K, Hotta Y, Nakayasu K, Yokoyama T, Takano T, Yamaguchi T, Kanai A. A new L527R mutation of the betaIGH3 gene in patients with lattice corneal dystrophy with deep stromal opacities. Hum Genet. 1998;103(3):286-9.
[34] Groenouw A. Knotchenformige Hornhauttrubungen (noduli corneae). Arch. Augenheilk. 1890. 21:281–289.
[35] Weidle E. Epitheliale und stromale Hornhautdystrophien. Der Ophthalmologe. 1996. 93:754–767.
[36] Witschel H. Hornhautdystrophien und Molekulargenetik. Der Ophthalmologe. 2002; 99(6):415–417.
[37] Smolin G., Thoft R. Corneal dystrophies and degeneration. The cornea / Third ed. Boston etc., 1994:499–524.
[38] Stewart HS, Ridgway AE, Dixon MJ, Bonshek R, Parveen R, Black G. Heterogeneity in granular corneal dystrophy: identification of three causative mutations in the TGFBI (BIGH3) gene-lessons for corneal amyloidogenesis. Hum Mutat. 1999;14(2):126-32.
[39] Holland EJ, Daya SM, Stone EM, Folberg R, Dobler AA, Cameron JD, Doughman DJ. Avellino corneal dystrophy. Clinical manifestations and natural history. Ophthalmology. 1992;99(10):1564-8.
[40] Akiya S, Takahashi H, Nakano N, Hirose N, Tokuda Y. Granular-lattice (Avellino) corneal dystrophy. Ophthalmologica. 1999;213(1):58-62.
[41] Rodrigues MM, Krachmer JH. Recent advances in corneal stromal dystrophies. Cornea. 1988;7(1):19-29.
[42] Ruusuvaara P, Setala K, Tarkkanen A. Granular corneal dystrophy with early stromal manifestation. A clinical and electron microscopical study. Acta Ophthalmol (Copenh). 1990;68(5):525-31.
[43] Okada M, Yamamoto S, Tsujikawa M, Watanabe H, Inoue Y, Maeda N, Shimomura Y, Nishida K, Quantock AJ, Kinoshita S, Tano Y. Two distinct kerato-epithelin mutations in Reis-B?cklers corneal dystrophy. Am J Ophthalmol. 1998;126(4):535-42.
[44] Rozzo C, Fossarello M, Galleri G, Sole G, Serru A, Orzalesi N, Serra A, Pirastu M. A common beta ig-h3 gene mutation (delta f540) in a large cohort of Sardinian Reis B?cklers corneal dystrophy patients. Mutations in brief no. 180. Online. Hum Mutat. 1998;12(3):215-6.
[45] Afshari NA, Mullally JE, Afshari MA, Steinert RF, Adamis AP, Azar DT, Talamo JH, Dohlman CH, Dryja TP. Survey of patients with granular, lattice, avellino, and Reis-Bucklers corneal dystrophies for mutations in the BIGH3 and gelsolin genes. Arch Ophthalmol. 2001;119(1):16-22.
[46] Weidle EG. Differential diagnosis of corneal dystrophies of the Groenouw I, Reis-B?ckler and Thiel-Behnke type. Fortschr Ophthalmol. 1989;86(4):265-71.
[47] Weidle EG. Honeycomb-shaped corneal dystrophy of Thiel and Behnke. Reclassification and distinction from reis-B?cklers' corneal dystrophy. Klin Monbl Augenheilkd. 1999;214(3):125-35.
[48] Yee RW, Sullivan LS, Lai HT, Stock EL, Lu Y, Khan MN, Blanton SH, Daiger SP. Linkage mapping of Thiel-Behnke corneal dystrophy (CDB2) to chromosome 10q23-q24. Genomics. 1997;46(1):152-4.
[49] Drozhzhina GI, Vit VV, Dumbrova NE. Molecular genetic, clinical and morphological analysis of patients with lattice corneal dystrophy, hereditary. Oftalmol Zh. 2002; 2:37–41.
[50] Maniatis T., Fritsch E. F., Sambrook J. Molecular cloning: a laboratory manual New York: Cold Spring Harbor Lab. publ., 1982 545 p.
[51] Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988;239(4839):487-91.
[52] Othenin-Girard P., Frueh-Epstein B., Gloor B. Identification of mutations in autosomal dominant corneal dystrophies. Invest. Ophthalmol. Vis. Sci. 1999. 40 (Suppl):563.