A novel mutation in transforming growth factor-beta induced protein (TGFβIp) reveals secondary structure perturbation in lattice corneal dystrophy. Issue 10 (10th August 2011)

• Record Type: Journal Article
• Authors: Lakshminarayanan, Rajamani; Vithana, Eranga N; Chai, Shu-Ming; Chaurasia, Shyam S; Saraswathi, Padhmanaban; Venkatraman, Anandalaksmi; Rojare, Camille; Venkataraman, Divya; Tan, Donald; Aung, Tin; Beuerman, Roger W; Mehta, Jodhbir S
• Is Part Of: British journal of ophthalmology. Volume 95:Issue 10(2011)
• Page Start: 1457
• Page End: 1462
• Publication Date: 2011-08-10
• Subjects: Cornea -- lattice corneal dystrophy -- TGFBI -- amyloid -- conformational stability -- experimental and 8211 animal models -- genetics -- imaging -- treatment lasers -- clinical trial -- experimental and 8211 laboratory; Ophthalmology -- Periodicals; 617.7
• DOI: 10.1136/bjophthalmol-2011-300651
• Languages: English
• ISSNs: 0007-1161

Abstract

Abstract : Background: To describe mutations in the transforming growth factor-beta induced ( TGFBI ) gene in Asian patients with Bowman's membrane as well as stromal corneal dystrophies, and to elucidate their structural implications, using model peptides. Methods: Twenty-two unrelated Asian families were examined clinically including visual acuity testing and ocular examination with slit lamp biomicroscopy. Genomic DNA was extracted and the 17 exons of the TGFBI gene were amplified by PCR and sequenced bi-directionally. Biophysical techniques were used to characterise the wild type and mutant model peptides. Results: Molecular genetic analysis identified a variety of mutations in our patient series including a novel heterozygous C to A transversion mutation in exon 14 (c.1859C→A), resulting in a substitution of a highly conserved alanine residue by aspartic acid (p.A620D). Clinical presentation in the patient with the p.A620D included subepithelial scarring in addition to the linear branching opacities usually seen with lattice dystrophy. Using model peptides, we showed that A620D mutant peptide alters the secondary structure and conformational stability, and increased amyloid formation. Conclusion: A novel mutation (A620D) in transforming growth factor-beta induced protein (TGFβIp) is described, expanding the repertoire of mutations in this protein. Using model peptides, we demonstrated that A→D substitution leads to perturbation of the secondary structure that may be responsible for the amyloid formation in lattice corneal dystrophy.