TGFBI – Granular Corneal Dystrophy Type II

Granular corneal dystrophy type II (GCD2) is an autosomal dominant stromal dystrophy caused by heterozygous mutations in the transforming growth factor beta-induced gene (TGFBI) leading to progressive opacification and vision impairment. The association between TGFBI and GCD2 meets Definitive clinical validity based on 117 patients (PMID:11095060) from 88 independent families (PMID:11095060), segregation of the recurrent R124H variant in multiple pedigrees, and concordant in vitro amyloidogenesis assays (PMID:12392546).

Genetic Evidence

Autosomal dominant inheritance with full penetrance in homozygotes and variable expressivity in heterozygotes. In one Chinese pedigree, 6 probands were heterozygous for c.371G>A (p.Arg124His) (PMID:19145249) with segregation in 5 additional affected relatives (PMID:19145249). The R124H missense variant is the predominant pathogenic allele; no loss-of-function or splice variants have been reported. Recurrent R124H arises in diverse populations without a clear founder effect, consistent with a mutational hotspot in exon 4 of TGFBI.

Functional Evidence

Mechanism: toxic gain-of-function by enhanced amyloidogenicity of mutant protein. In vitro, peptides bearing His124 form significantly more β-pleated sheets and amyloid fibrils than wild-type (PMID:12392546). Cellular models of mutant TGFBIp demonstrate deposition of insoluble aggregates in corneal stroma analogs, mirroring the human phenotype.

Conflicting Evidence

No studies have convincingly refuted the pathogenic role of R124H in GCD2; reduced penetrance has been observed for heterozygotes but is due to age-dependent expressivity rather than non-pathogenicity (PMID:19145249).

Conclusion

The c.371G>A (p.Arg124His) variant in TGFBI has a definitive gene-disease association with granular corneal dystrophy type II. Genetic testing for R124H enables accurate diagnosis, informs prognosis, and guides patient management.

References

• Human mutation • 1999 • Heterogeneity in granular corneal dystrophy: identification of three causative mutations in the TGFBI (BIGH3) gene—lessons for corneal amyloidogenesis PMID:10425035
• Cornea • 2000 • Six different mutations of TGFBI (betaig-h3, keratoepithelin) gene found in Japanese corneal dystrophies PMID:11095060
• European journal of biochemistry • 2002 • BIGH3 (TGFBI) Arg124 mutations influence the amyloid conversion of related peptides in vitro PMID:12392546
• Molecular vision • 2009 • Reduced penetrance in familial Avellino corneal dystrophy associated with TGFBI mutations PMID:19145249

Evidence Based Scoring (AI generated)