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Biochemical mechanisms of aggregation in TGFBI-linked corneal dystrophies.
Prog Retin Eye Res. 2020 Jan 29 [Online ahead of print]PR

Abstract

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.

Authors+Show Affiliations

Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, the Netherlands.Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, UK; Avellino Labs USA, Menlo Park, USA.Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.Avellino Labs USA, Menlo Park, USA.QIAGEN Aarhus A/S, Aarhus, Denmark.Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, UK; Avellino Labs USA, Menlo Park, USA.Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark; Interdisciplinary Nanoscience Centre (iNANO), Aarhus University, Aarhus, Denmark.Department of Ophthalmology, Aarhus University Hospital, Aarhus, Denmark.Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark. Electronic address: jje@mbg.au.dk.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

32004730

Citation

Nielsen, Nadia Sukusu, et al. "Biochemical Mechanisms of Aggregation in TGFBI-linked Corneal Dystrophies." Progress in Retinal and Eye Research, 2020, p. 100843.
Nielsen NS, Poulsen ET, Lukassen MV, et al. Biochemical mechanisms of aggregation in TGFBI-linked corneal dystrophies. Prog Retin Eye Res. 2020.
Nielsen, N. S., Poulsen, E. T., Lukassen, M. V., Chao Shern, C., Mogensen, E. H., Weberskov, C. E., DeDionisio, L., Schauser, L., Moore, T. C. B., Otzen, D. E., Hjortdal, J., & Enghild, J. J. (2020). Biochemical mechanisms of aggregation in TGFBI-linked corneal dystrophies. Progress in Retinal and Eye Research, 100843. https://doi.org/10.1016/j.preteyeres.2020.100843
Nielsen NS, et al. Biochemical Mechanisms of Aggregation in TGFBI-linked Corneal Dystrophies. Prog Retin Eye Res. 2020 Jan 29;100843. PubMed PMID: 32004730.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Biochemical mechanisms of aggregation in TGFBI-linked corneal dystrophies. AU - Nielsen,Nadia Sukusu, AU - Poulsen,Ebbe Toftgaard, AU - Lukassen,Marie V, AU - Chao Shern,Connie, AU - Mogensen,Emilie Hage, AU - Weberskov,Christian E, AU - DeDionisio,Larry, AU - Schauser,Leif, AU - Moore,Tara C B, AU - Otzen,Daniel E, AU - Hjortdal,Jesper, AU - Enghild,Jan J, Y1 - 2020/01/29/ PY - 2019/11/07/received PY - 2020/01/17/revised PY - 2020/01/23/accepted PY - 2020/2/1/pubmed PY - 2020/2/1/medline PY - 2020/2/1/entrez KW - CRISPR/Cas9 KW - Corneal dystrophies KW - Protein aggregation KW - TGFBI gene KW - TGFBIp KW - human cornea SP - 100843 EP - 100843 JF - Progress in retinal and eye research JO - Prog Retin Eye Res N2 - 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. SN - 1873-1635 UR - https://www.unboundmedicine.com/medline/citation/32004730/Biochemical_mechanisms_of_aggregation_in_TGFBI-linked_corneal_dystrophies L2 - https://linkinghub.elsevier.com/retrieve/pii/S1350-9462(20)30015-X DB - PRIME DP - Unbound Medicine ER -
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