TGFBI – Thiel-Behnke Corneal Dystrophy

Thiel-Behnke corneal dystrophy (MONDO:0011185) is an autosomal dominant disorder characterized by honeycomb-like subepithelial corneal opacities and recurrent erosions (HP:0009023; HP:0007958). The transforming growth factor β-induced gene TGFBI (HGNC:11771) encodes an extracellular matrix protein (keratoepithelin) critical for corneal transparency.

Heterozygous missense variants c.1663C>T (p.Arg555Trp) and c.370C>T (p.Arg124Cys) co-segregate with Thiel-Behnke corneal dystrophy in a four-generation Chinese pedigree and in two additional Chinese families, respectively ([PMID:26464103]; [PMID:19433713]). In total, 18 affected individuals across 3 families demonstrate complete penetrance, absence of these variants in unaffected relatives and controls, and clear autosomal dominant segregation ([PMID:26464103]; [PMID:19433713]).

Functional assays reveal that peptides bearing Arg124Cys exhibit accelerated amyloid conversion and increased β-pleated sheet content in vitro, modulated by Val112-Val113 interactions ([PMID:12392546]). Overexpression of mutant TGFBIp (R124C, R555W) in human corneal epithelial and HeLa cells induces caspase-3–dependent apoptosis, supporting a toxic gain-of-function mechanism congruent with the human phenotype ([PMID:12824240]).

Histopathology of keratoplasty specimens shows eosinophilic, Congo red–positive deposits in Bowman's layer that do not stain with PAS or Masson's trichrome, matching the clinical honeycomb pattern ([PMID:26464103]). These findings align with amyloidogenic pathology driven by specific missense mutations in TGFBI.

No studies dispute the association between TGFBI and Thiel-Behnke corneal dystrophy. Genotype–phenotype correlations are consistent: Arg555Trp and Arg124Cys localize to the fourth and first fasciclin domains, respectively, and produce a characteristic histological signature.

Integration of robust segregation data and convergent functional evidence supports a strong autosomal dominant association between TGFBI and Thiel-Behnke corneal dystrophy. Additional allelic variants in TGFBI underlie other corneal dystrophies but do not weaken the TBCD link.

Key Take-home: Pathogenic TGFBI missense variants cause autosomal dominant Thiel-Behnke corneal dystrophy via amyloidogenic gain-of-function, supporting targeted genetic testing and variant-specific therapeutics.

References

• BMC Ophthalmology • 2015 • A novel phenotype-genotype correlation with an Arg555Trp mutation of TGFBI gene in Thiel-Behnke corneal dystrophy in a Chinese pedigree. PMID:26464103
• Archives of Ophthalmology • 2009 • Arg124Cys mutation of the TGFBI gene in 2 Chinese families with Thiel-Behnke corneal dystrophy. PMID:19433713

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