Biochemical mechanisms of aggregation in TGFBI-linked corneal dystrophies

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.

Spatiotemporal Characterization of Anterior Segment Mesenchyme Heterogeneity During Zebrafish Ocular Anterior Segment Development

“…Tgfbi is associated with head mesenchyme and neural crest and is also predicted to be localized to the extracellular matrix (Chakravarthi et al, 2005;Kannabiran and Klintworth, 2006). Interestingly, the tgfbi gene is associated with a subset of familial corneal dystrophies (Nielsen et al, 2020). Hmgn2 is a non-histone component of nucleosomal DNA and is associated with transcriptionally active chromatin, especially in cells that remain undifferentiated, and is involved in DNA replication, transcription, and repair (Lucey et al, 2008;Furusawa and Cherukuri, 2010). Although not yet associated with AS development or ASD pathology, hmgn2 is abundantly expressed throughout the ocular structures of the AS and retina in mice, especially in the lens fibers and epithelium layer of the cornea (Lucey et al, 2008).…”

Mutation-induced dimerization of transforming growth factor-β–induced protein may drive protein aggregation in granular corneal dystrophy

“…To date, 74 mutations in the transforming growth factor-β–induced ( TGFBI ) gene have been associated with the group of rare autosomal dominant diseases, TGFBI -linked corneal dystrophies (CDs) ( 1 ). The prevalence of TGFBI -linked CDs in the Chinese and Korean populations is 1 in 416 and 1 in 870, respectively ( 2 , 3 ).…”

“…The principal constituent of the protein deposits is one of the most abundant proteins in the extracellular matrix (ECM) of the human cornea, transforming growth factor-β–induced protein (TGFBIp) ( 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ). The function of corneal TGFBIp is elusive, but its ability to bind both integrins and ECM molecules indicates a role in cell adhesion ( 1 ).…”

“…The four FAS1 domains contain both α-helices and β-sheets arranged in the order α1-α3 + β1 + α4-α6 + β2-β8 ( 16 ). The 74 identified pathogenic mutations are distributed throughout the domains of TGFBIp, but not evenly; 57 are found within the FAS1-4 domain and ten within the FAS1-1 domain ( 1 ). Arg124 of the FAS1-1 domain and Arg555 of the FAS1-4 domain have been classified as mutational hot spots owing to the frequency of individual pathogenic mutations observed in patients at these sites.…”

Effect of osmolytes on in-vitro aggregation properties of peptides derived from TGFBIp

“…TGFBIp consists of a secretory signal peptide, a domain rich in cysteine residues, a cell attachment tripeptide Arg-Gly-Asp (RGD) signal residue, and four Fasciclin 1 (FAS-1) domains 9,10 . The TGFBI gene has 74 mutations reported to date 11 , and the mutant protein is associated with modified protein stability, altered proteolytic processing, and deposition of insoluble aggregates in various layers of the cornea [12][13][14][15][16] . The aggregation and deposition of TGFBIp display different clinical phenotypes; the deposits range from amyloidogenic structures to amorphous granular deposits, or a combination of both 17 .…”