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.
Prog Retin Eye Res. 2020 Jul;77:100843. doi: 10.1016/j.preteyeres.2020.100843. Epub 2020 Jan 29.
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.
转化生长因子-β诱导蛋白（TGFBIp）是细胞外基质蛋白，是角膜基质中第二丰富的蛋白质。在这篇综述中，我们总结了目前关于人 TGFBIp 的表达、分子结构、结合伴侣和功能的知识。迄今为止，转化生长因子-β诱导基因（TGFBI）中的 74 种突变与 TGFBI 相关角膜营养不良中的淀粉样和无定形蛋白沉积有关。我们讨论了目前对 TGFBI 相关角膜营养不良的生化机制的理解，并提出导致颗粒状角膜营养不良（GCD）的突变降低了 TGFBIp 的溶解度，并影响了 TGFBIp 与角膜基质成分之间的相互作用，而与格子状角膜营养不良（LCD）相关的突变导致蛋白质的不稳定性，破坏了蛋白水解的周转率，特别是丝氨酸蛋白酶 HtrA1。未来的研究应集中在 TGFBIp 在角膜中的功能、体内生化机制的证实以及疾病模型的开发上。未来针对 TGFBI 相关角膜营养不良的治疗方法可能包括调节蛋白聚集的局部制剂或使用 CRISPR/Cas9 技术针对突变等位基因的基因治疗。
