Biochemical mechanisms of aggregation in TGFBI-linked corneal dystrophies

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperReviewResearchpeer-review

  • Nadia Sukusu Nielsen
  • Ebbe Toftgaard Poulsen
  • Marie V Lukassen, Biomolecular Mass Spectrometry and Proteomics, Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Utrecht, the Netherlands.
  • ,
  • Connie Chao Shern, Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, UK; Avellino Labs USA, Menlo Park, USA.
  • ,
  • Emilie Hage Mogensen
  • Christian E Weberskov
  • Larry DeDionisio, Avellino Labs USA, Menlo Park, USA.
  • ,
  • Leif Schauser, QIAGEN Aarhus A/S, Aarhus, Denmark.
  • ,
  • Tara C B Moore, Biomedical Sciences Research Institute, Ulster University, Coleraine, Northern Ireland, UK; Avellino Labs USA, Menlo Park, USA.
  • ,
  • Daniel E Otzen
  • Jesper Hjortdal
  • Jan J Enghild

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.

Original languageEnglish
JournalProgress in Retinal and Eye Research
Pages (from-to)100843
ISSN1350-9462
DOIs
Publication statusE-pub ahead of print - 28 Jan 2020
Externally publishedYes

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