Abstract

Several corneal dystrophies [granular corneal dystrophy (GCD), lattice corneal dystrophy (LCD) types I and IIIA, combined UCD-LCD type I, Thiel-Behnke dystrophy and Reis-Bucklers dystrophy] have been found to result from mutations in BIGH3. These conditions are characterized by the deposition within the cornea of proteins that react with antibodies to beta-ig-h3 (the protein product of the BIGH3 gene). For each dystrophy the accumulations have a characteristic ultrastructure. This proposal is to purify and characterize beta-ig-h3 from plasma of persons with and without different BIGH3 corneal dystrophies and from cell cultures of COS- 7, CHO-K1 and baculovirus infected insect cells transfected with vectors containing the mutations that produce BIGH3 corneal dystrophies. Wild-type and mutant beta-ig-h3 proteins will be compared to test the hypothesis that the structure of the proteins that accumulate within the cornea in the BIGH3 corneal dystrophies are related to the mutated protein and that a relationship exists between different phenotypes and the BIGH3 genotypes and between the amount of the mutant protein that is expressed. The nature of the amyloid that accumulates in certain BIGH3 corneal dystrophies and the reason for its production will be investigated. We will determine whether BIGH3 related amyloid is a specific fragment of mutant beta-ig-h3. Because beta-ig-h3 interacts with components of the extracellular matrix we will attempt to identify protein- protein interactions that may account for the accumulations that characterize the BIGH3 corneal dystrophies. The biosynthesis of beta-ig-h3 will be characterized in rabbit corneal epithelial cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012712-03
Application #
6384836
Study Section
Visual Sciences A Study Section (VISA)
Program Officer
Fisher, Richard S
Project Start
1999-08-01
Project End
2004-07-31
Budget Start
2001-08-01
Budget End
2002-07-31
Support Year
3
Fiscal Year
2001
Total Cost
$255,437
Indirect Cost

  Institution

Name
Duke University
Department
Pathology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705

  Publications

Sørensen, Charlotte S; Runager, Kasper; Scavenius, Carsten et al. (2015) Fibril Core of Transforming Growth Factor Beta-Induced Protein (TGFBIp) Facilitates Aggregation of Corneal TGFBIp. Biochemistry 54:2943-56
Koldsø, Heidi; Andersen, Ole Juul; Nikolajsen, Camilla Lund et al. (2015) Early Events in the Amyloid Formation of the A546T Mutant of Transforming Growth Factor ?-Induced Protein in Corneal Dystrophies Compared to the Nonfibrillating R555W and R555Q Mutants. Biochemistry 54:5546-56
Nielsen, Nadia Sukusu; Poulsen, Ebbe Toftgaard; Klintworth, Gordon K et al. (2014) Insight into the Protein Composition of Immunoglobulin Light Chain Deposits of Eyelid, Orbital and Conjunctival Amyloidosis. J Proteomics Bioinform Suppl 8:
Risør, Michael W; Poulsen, Ebbe Toftgaard; Thomsen, Line R et al. (2014) The autolysis of human HtrA1 is governed by the redox state of its N-terminal domain. Biochemistry 53:3851-7
Poulsen, Ebbe Toftgaard; Runager, Kasper; Risør, Michael W et al. (2014) Comparison of two phenotypically distinct lattice corneal dystrophies caused by mutations in the transforming growth factor beta induced (TGFBI) gene. Proteomics Clin Appl 8:168-77
Poulsen, Ebbe Toftgaard; Dyrlund, Thomas F; Runager, Kasper et al. (2014) Proteomics of Fuchs' endothelial corneal dystrophy support that the extracellular matrix of Descemet's membrane is disordered. J Proteome Res 13:4659-67
Runager, Kasper; Klintworth, Gordon K; Karring, Henrik et al. (2013) The insoluble TGFBIp fraction of the cornea is covalently linked via a disulfide bond to type XII collagen. Biochemistry 52:2821-7
Karring, Henrik; Poulsen, Ebbe Toftgaard; Runager, Kasper et al. (2013) Serine protease HtrA1 accumulates in corneal transforming growth factor beta induced protein (TGFBIp) amyloid deposits. Mol Vis 19:861-76
Underhaug, Jarl; Koldsø, Heidi; Runager, Kasper et al. (2013) Mutation in transforming growth factor beta induced protein associated with granular corneal dystrophy type 1 reduces the proteolytic susceptibility through local structural stabilization. Biochim Biophys Acta 1834:2812-22
Semba, Richard D; Enghild, Jan J; Venkatraman, Vidya et al. (2013) The Human Eye Proteome Project: perspectives on an emerging proteome. Proteomics 13:2500-11

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