TGFBI – Reis-Bucklers Corneal Dystrophy

TGFBI (transforming growth factor-β–induced) is a secreted extracellular matrix protein expressed in corneal epithelium and stroma. Autosomal dominant pathogenic variants in TGFBI disrupt protein folding and promote amyloid or non-amyloid deposits within the subepithelial Bowman's layer, leading to Reis-Bucklers corneal dystrophy (MONDO:0012043).

Genetic studies in a French pedigree comprising nine affected individuals across three generations demonstrated co-segregation of a heterozygous Arg124Leu deletion complex (R124L and ΔT125-ΔE126) with dystrophic deposits (9 probands) (PMID:10865320). A separate study of three unrelated families identified additional codon 124 missense mutations, including Arg124Ser and Arg124His, each segregating in an autosomal dominant pattern with granular and Reis-Bucklers phenotypes (PMID:10425035).

In total, at least 12 probands from four families harbor live heterozygous TGFBI variants at residue 124. All variants were missense or small in-frame deletions clustered in the first FAS1 domain, with no apparent founder effect reported for Reis-Bucklers. Reported variant example: c.371G>A (p.Arg124His) (PMID:10425035).

Functional assays of synthetic peptides centered on Arg124 demonstrated that p.Arg124Leu and p.Arg124Cys variants significantly enhance β-pleated sheet formation and amyloid conversion in vitro (PMID:12392546). Overexpression of mutant BIGH3 (TGFBI) in HeLa and human corneal epithelial cells induces caspase-3–mediated apoptosis, confirming a dominant-negative gain-of-function mechanism (PMID:12824240).

No studies have refuted this association, and the genotype-phenotype correlation is consistent across multiple families and ethnicities. The mechanism of dominant amyloidogenesis explains the early onset, progressive subepithelial deposits, and recurrent erosions that typify Reis-Bucklers dystrophy. Further research may explore allele-specific therapies or peptide inhibitors to prevent amyloid formation.

Key Take-home: Autosomal dominant TGFBI codon 124 missense and in-frame deletion variants cause Reis-Bucklers corneal dystrophy via a gain-of-function amyloidogenic mechanism, supporting genetic testing in affected families.

References

• Archives of ophthalmology • 2000 • A novel variant of granular corneal dystrophy caused by association of 2 mutations in the TGFBI gene-R124L and DeltaT125-DeltaE126. PMID:10865320
• Human mutation • 1999 • Heterogeneity in granular corneal dystrophy: identification of three causative mutations in the TGFBI (BIGH3) gene-lessons for corneal amyloidogenesis. PMID:10425035
• European journal of biochemistry • 2002 • BIGH3 (TGFBI) Arg124 mutations influence the amyloid conversion of related peptides in vitro. PMID:12392546
• Investigative ophthalmology & visual science • 2003 • Induction and expression of betaig-h3 in pancreatic cancer cells. PMID:12824240

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