Biochemical mechanisms of aggregation in TGFBI-linked corneal dystrophies.

Autor: Nielsen NS; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark., Poulsen ET; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark., Lukassen MV; Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, the Netherlands., Chao Shern C; Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, UK; Avellino Labs USA, Menlo Park, USA., Mogensen EH; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark., Weberskov CE; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark., DeDionisio L; Avellino Labs USA, Menlo Park, USA., Schauser L; QIAGEN Aarhus A/S, Aarhus, Denmark., Moore TCB; Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, UK; Avellino Labs USA, Menlo Park, USA., Otzen DE; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark; Interdisciplinary Nanoscience Centre (iNANO), Aarhus University, Aarhus, Denmark., Hjortdal J; Department of Ophthalmology, Aarhus University Hospital, Aarhus, Denmark., Enghild JJ; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark. Electronic address: jje@mbg.au.dk.
Jazyk: angličtina
Zdroj: Progress in retinal and eye research [Prog Retin Eye Res] 2020 Jul; Vol. 77, pp. 100843. Date of Electronic Publication: 2020 Jan 29.
DOI: 10.1016/j.preteyeres.2020.100843
Abstrakt: Transforming growth factor-β-induced protein (TGFBIp), an extracellular matrix protein, is the second most abundant protein in the corneal stroma. In this review, we summarize the current knowledge concerning the expression, molecular structure, binding partners, and functions of human TGFBIp. To date, 74 mutations in the transforming growth factor-β-induced gene (TGFBI) are associated with amyloid and amorphous protein deposition in TGFBI-linked corneal dystrophies. We discuss the current understanding of the biochemical mechanisms of TGFBI-linked corneal dystrophies and propose that mutations leading to granular corneal dystrophy (GCD) decrease the solubility of TGFBIp and affect the interactions between TGFBIp and components of the corneal stroma, whereas mutations associated with lattice corneal dystrophy (LCD) lead to a destabilization of the protein that disrupts proteolytic turnover, especially by the serine protease HtrA1. Future research should focus on TGFBIp function in the cornea, confirmation of the biochemical mechanisms in vivo, and the development of disease models. Future therapies for TGFBI-linked corneal dystrophies might include topical agents that regulate protein aggregation or gene therapy that targets the mutant allele by CRISPR/Cas9 technology.
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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