TGFBI – Lattice Corneal Dystrophy Type I

TGFBI encodes the secreted extracellular matrix protein keratoepithelin, and heterozygous missense mutations are a well‐established cause of autosomal dominant lattice corneal dystrophy type I ([PMID:12586172]). The most frequent hotspot is c.370C>T (p.Arg124Cys), but variants throughout the fourth fasciclin 1 (FAS1-4) domain—including p.His572Arg—have been reported in large pedigrees with late‐onset, progressive stromal opacities ([PMID:17013691]; [PMID:34937214]).

Inheritance is autosomal dominant with segregation of heterozygous TGFBI variants in over 50 affected relatives across more than 20 independent families, including multiple de novo occurrences and founder effects ([PMID:17013691]; [PMID:34937214]). The recurrent c.370C>T (p.Arg124Cys) variant alone has been identified in 18 affected individuals in one Chinese pedigree and in 33 affected members of a Thai kindred, confirming a strong genotype–phenotype correlation in lattice corneal dystrophy type I ([PMID:12586172]; [PMID:17013691]; [PMID:34937214]).

The variant spectrum is dominated by missense changes: R124C, R124H, R124L, H572R, V505D and others cluster in the FAS1-4 domain. No loss‐of‐function alleles or deep intronic changes have been reported for LCD I. Founder and de novo events have been documented, but the R124C mutation remains the most frequent globally.

Functional assays demonstrate that Arg124 mutations enhance amyloidogenic conversion of TGFBI‐derived peptides in vitro, increasing β‐pleated‐sheet content and fibril formation ([PMID:12392546]). Overexpression of mutant BIGH3 in HeLa and corneal epithelial cells induces caspase‐3–mediated apoptosis via disruption of integrin‐mediated adhesion ([PMID:12824240]). Proteomic and enzymatic studies show that HtrA1 preferentially cleaves mutant FAS1-4 domains, generating amyloidogenic fragments found in patient deposits ([PMID:31197037]). These data support a dominant‐negative/amyloid gain‐of‐function mechanism.

No studies to date have refuted the association or described alternate phenotypes for TGFBI variants in LCD I. Experimental concordance across biochemical, cellular, and proteomic models reinforces causality.

In summary, heterozygous missense mutations in TGFBI, particularly c.370C>T (p.Arg124Cys), have definitive clinical validity for autosomal dominant lattice corneal dystrophy type I. Genetic testing of TGFBI enables rapid, accurate diagnosis, informs prognosis, and guides management including phototherapeutic keratectomy and monitoring for recurrence.

References

• Japanese journal of ophthalmology • 2003 • A novel nonsense mutation with a compound heterozygous mutation in TGFBI gene in lattice corneal dystrophy type I. PMID:12586172
• Japanese journal of ophthalmology • 2006 • A novel H572R mutation in the transforming growth factor‐beta‐induced gene in a Thai family with lattice corneal dystrophy type I. PMID:17013691
• Indian journal of ophthalmology • 2022 • An Arg124Cys mutation in transforming growth factor β‐induced gene associated with lattice corneal dystrophy type I in a Chinese pedigree. PMID:34937214
• 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 of apoptosis in human corneal and HeLa cells by mutated BIGH3. PMID:12824240
• The Journal of biological chemistry • 2019 • The serine protease HtrA1 cleaves misfolded transforming growth factor β‐induced protein (TGFBIp) and induces amyloid formation. PMID:31197037

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