Transforming Growth Factor Beta-Induced Corneal Dystrophies

Transforming growth factor beta-induced corneal dystrophies are a heterogeneous group of inherited disorders characterised by progressive deposition of protein aggregates within the corneal stroma and epithelium, leading to visual impairment. These conditions arise from dominant mutations in the TGFBI gene, which encodes an extracellular matrix protein (TGFBIp) comprising an N-terminal EMI domain and four conserved fasciclin 1 (FAS1) domains. Mutations at key residues, notably Arg-124 and Arg-555, perturb the stability and turnover of the FAS1 domains, promoting either amyloid or amorphous aggregate formation. The resulting deposits scatter light and compromise corneal transparency. Beyond structural consequences, aberrant interactions of mutant TGFBIp with integrins and other matrix components disrupt cell adhesion, migration and wound healing. Recent advances have elucidated the underlying molecular mechanisms—from domain stability and aggregate architecture to chaperone-mediated disassembly—and have led to novel in vivo models. Together, these insights underpin emerging strategies for improved genetic diagnostics, pre-surgical screening and targeted therapeutic intervention aimed at restoring corneal clarity.

Research from Nature Portfolio

Recent studies have uncovered an ATP-independent chaperone mechanism capable of disaggregating TGFBIp amyloids in ex vivo human corneal tissue. By combining cryo-EM and NMR, researchers modelled the interaction between L-PGDS and structurally frustrated regions of TGFBIp fibrils, revealing how release of conformational strain drives local fibre breakage. This work suggests a non-canonical energy source for amyloid clearance and highlights chaperone-based therapies for protein-deposition diseases. Complementing these findings, a genetically engineered mouse carrying the R124C mutation reproduces key features of lattice corneal dystrophy, including stromal opacity and delayed epithelial wound healing. Quantitative analysis demonstrated increased corneal accumulation of mutant TGFBIp and ultrastructural deposits, validating this model for preclinical testing of anti-aggregation and gene-editing approaches.

Transforming Growth Factor Beta-Induced Corneal Dystrophies publication trend

The graph below shows the total number of articles in transforming growth factor beta-induced corneal dystrophies across all publications each year (not limited to Nature Index journals).

Technical terms

Corneal dystrophy: inherited disorder of the cornea characterised by progressive deposition of extracellular material and loss of transparency.

Transforming growth factor beta: multifunctional cytokine that regulates cell growth, differentiation and extracellular matrix production.

TGFBI: gene encoding TGF-β-induced protein, a matrix component essential for corneal structure and cell adhesion.

FAS1 domain: repetitive fasciclin 1 motifs within TGFBIp that mediate protein–protein interactions and influence stability.

Amyloid fibrils: insoluble protein aggregates with a characteristic cross-β sheet architecture implicated in degenerative disorders.

References

1. Release of frustration drives corneal amyloid disaggregation by brain chaperone. Communications Biology (2023).
2. Evaluation of TGFBI corneal dystrophy and molecular diagnostic testing. Eye (2019).
3. Identification of Motifs in the Fasciclin Domains of the Transforming Growth Factor-β-induced Matrix Protein βig-h3 That Interact with the αvβ5 Integrin*. Journal of Biological Chemistry (2002).
4. Human Phenotypically Distinct TGFBI Corneal Dystrophies Are Linked to the Stability of the Fourth FAS1 Domain of TGFBIp*. Journal of Biological Chemistry (2010).
5. Amyloid and Non-amyloid Forms of 5q31-linked Corneal Dystrophy Resulting from Kerato-epithelin Mutations at Arg-124 Are Associated with Abnormal Turnover of the Protein*. Journal of Biological Chemistry (2000).
6. Generation of mouse model of TGFBI-R124C corneal dystrophy using CRISPR/Cas9-mediated homology-directed repair. Scientific Reports (2020).