Purpose: To report a novel L558P mutation of the human transforming growth factor β-induced (TGFBI) gene found in Ukrainian families with atypical corneal dystrophy (CD). Methods: Genomic DNA was extracted from peripheral leukocytes of 12 members of 4 unrelated families with atypical CD. We performed genotype analysis of these families with microsatellite markers surrounding the TGFBI locus. Exons of the TGFBI gene were amplified by polymerase chain reaction (PCR), and directly sequenced in 5 patients of 4 unrelated families. We utilized a simple PCR/restriction fragment length polymorphism-based technique for L558P mutation identification. Fifty normal individuals were also analyzed as controls. These assays were complemented by histological analysis of available corneal buttons excised during penetrating keratoplasty. Results: A heterozygous single-base-pair transition (CTC to CCC, leucine to proline) at codon 558 in exon 12 of the TGFBI gene (L558P) was detected in 10 individuals. Eight are affected, and 2 are teenagers with no clinical manifestation of the disease as yet. The mutation was not found in 2 healthy individuals from 2 high-risk CD families, nor in 50 normal controls. Histopathological examination identified amyloid deposits, mostly in the posterior central cornea. Haplotype analysis provided evidence of a common founder of the L558P mutation. The mutation works on the protein level by disrupting an α-helix, which is crucial for the normal functioning of keratoepithelin. Conclusion: A novel L558P mutation in the TGFBI gene causes an atypical type of stromal CD.

Waring G, Rodrigues M, Laibson R: Corneal dystrophy: dystrophies of the epithelium, Bowman layer and stromas. Surv Opthalmol 1978;23:97–101.
Weidle E: Epitheliale und stromale Hornhautdystrophien. Ophthalmologe 1996;93:754–767.
Munier FL, Korvatska E, Djemai A, Palsier DL, Zografos L, Pescia G, Schorderet DF: Keratoepithelin mutations in four 5g31-linked corneal dystrophies. Nat Genet 1997;15:247–251.
Klintworth GK: Advances in the molecular genetics of corneal dystrophies. Am J Ophthalmol 1999;128:747–754.
Kannabiran C, Klintworth GK: TGFBI gene mutations in corneal dystrophies. Hum Mutat 2006;27:615–625.
Klintworth GK, Bao W, Afshari NA: Two mutations in the TGFBI (BIGH3) gene associated with lattice corneal dystrophy in an extensively studied family. Invest Ophthalmol Vis Sci 2004;45:1382–1388.
Munier FL, Frueh BE, Othenin-Girard P, Uffer S, Cousin P, Wang MX, Black GCM, Blasi MA, Balestrazzi E, Lorenz B, Escoto R, Barraquer R, Hoeltzenbein M, Gloor B, Fossarello M, Singh AD, Arsenijevic Y, Zografos L, Schorderet D: BIGH3 mutation spectrum in corneal dystrophies. Invest Ophthalmol Vis Sci 2002;43:949–954.
Aldave AJ, Rayner SA, Kim BT, Prechanond A, Yellore VS: Unilateral lattice corneal dystrophy associated with the novel His572del mutation in the TGFBI gene. Mol Vis 2006;12:142–146.
Takacs L, Losonczy G, Matesz K, Balogh I, Sohajda Z, Toth K, Fazakas F, Vereb G, Berta A: TGFBI (BIGH3) gene mutations in Hungary – report of the novel F547S mutation associated with polymorphic corneal amyloidosis. Mol Vis 2007;13:1976–1983.
Stix B, Leber M, Bingemer P, Gross C, Ruschoff J, Fandrich M, Schorderet DF, Vorwerk CK, Zacharias M, Roessner, Rocken C: Hereditary lattice corneal dystrophy is associated with corneal amyloid deposits enclosing C-terminal fragments of keratoepithelin. Invest Ophthalmol Vis Sci 2005;46:1133–1139.
Korvatska E, Munier FL, Zografos L, Ahmad F, Faggioni R, Dolivo-Beuret A, Uffer S, Pescia G, Schorderet DF: 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 1996;4:214–218.
Guex N, Peitsch MC: SWISS-MODEL and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 1997;18:2714–2723.
Yoneyama M, Tomizawa T, Tochio N, Koshiba S, Inoue M, Kigawa T, Yokoyama S: Solution structure of the FAS1 domain of human transforming growth factor-beta induced protein Ig-h3. In submission.
Pampukha VM, Drozhyna GI, Livshits LA: TGFBI gene mutation analysis in families with hereditary corneal dystrophies from Ukraine. Opthalmologica 2004;218:411–414.
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;41:1302–1308.
Park KS, Shin HD, Park BL, Cheong HS, Cho YM, Lee HK, Lee JY, Lee JK, Kim HT, Han BG, Kim JW, Koh IS, Kim YJ, Kimm K, Oh B: Genetic polymorphisms in the transforming growth factor beta-induced gene associated with BMI. Hum Mutat 2005;25:322.
Huang QY, Xu FH, Shen H, Deng HY, Liu YJ, Liu YZ, Li JL, Recker RR, Deng HW: Mutation pattern at dinuceotide microsatellite loci in humans. Hum Genet 2002;70:625–634.
Brinkmann B, Klintschar M, Neuhuber F, Hühne J, Rolf B: Mutation rate in human microsatellites: influence of the structure and length of the tandem repeat. Am J Hum Genet 1998;62:1408–1514.
Kayser M, Roewer L, Hedman M, Henke L, Henke J, Brauer S, Krüger C, Krawczak M, Nagy M, Dobosz T, Szibor R, de Knijff P, Stoneking M, Sajantila A: Characteristic and frequency of germline mutations at microsatellite loci from the human Y chromosome, as revealed by direct observation in father/son pairs. Am J Hum Genet 2000;66:1580–1588.
Clout NJ, Hohenester E: A model of FAS1 domain 4 of the corneal protein βig-h3 gives a clearer view on corneal dystrophies. Mol Vis 2003;9:440–448.
Van Der Spoel D, Lindhal E, Hess B, Groenhof G, Mark AE, Berendsen HJ: GROMACS: fast, flexible, and free. J Comput Chem 2005;26:1701–1718.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.