TGFBI – Granular Corneal Dystrophy Type I

Granular corneal dystrophy type I (GCD1) is an autosomal dominant disorder characterized by progressive grayish‐white opacities in the anterior stroma leading to visual impairment.[PMID:30915236] Mutations in the transforming growth factor β–induced gene (TGFBI) underlie GCD1 by perturbing the fourth fasciclin domain (FAS1‐4), altering protein stability and promoting aberrant aggregation.

Genetic Evidence

Multiple unrelated pedigrees of diverse ethnicities demonstrate co‐segregation of heterozygous TGFBI variants with GCD1 in over 47 affected individuals[PMID:30915236][PMID:31322463][PMID:27829782]. A hotspot missense mutation, c.1663C>T (p.Arg555Trp), recurs in Chinese and Turkish families and is absent from controls,[PMID:18752451][PMID:27829782] while p.Ala546Asp and p.Arg124Ser have also been reported in large pedigrees.[PMID:18752451][PMID:31322463] Penetrance is high (75–100%) and multiple families show clear dominant transmission without unaffected carriers.

Variant Spectrum

Pathogenic variants cluster in exon 12 affecting residues 546 and 555 and in exon 4 affecting residue 124. The recurrent c.1663C>T (p.Arg555Trp) accounts for the majority of cases across populations. Other missense alleles include c.1636G>A (p.Ala546Thr), c.370C>T (p.Arg124Cys), and c.370C>T (p.Arg124Ser) with genotype–phenotype correlations for homozygous versus heterozygous states.[PMID:31322463]

Functional Evidence

Biophysical studies show that p.Arg555Trp increases local structural stability, burying Trp555 in a hydrophobic pocket and reducing proteolytic susceptibility, which leads to accumulation of amyloidogenic fragments in vitro.[PMID:24129074] Overexpression of mutated TGFBIp in corneal epithelial cells induces caspase‐3–mediated apoptosis, consistent with tissue damage observed in patients.[PMID:12824240] Furthermore, stability assays rank FAS1‐4 variants by aggregation propensity, linking in vitro behavior to clinical phenotype.[PMID:21135107]

Conflicting Evidence

No published reports refute the association; all functional and genetic data are concordant.

Integration & Clinical Utility

TGFBI mutations cause GCD1 via a dominant gain‐of‐function mechanism that promotes FAS1‐4 domain stabilization, impaired turnover, and deposition of insoluble aggregates. Genetic testing for known hotspot variants (e.g., p.Arg555Trp) enables definitive diagnosis and informs prognosis for surgical or emerging pharmacologic interventions. Key take‐home: TGFBI screening is critical for accurate diagnosis, genetic counseling, and management of granular corneal dystrophy type I.

References

• Journal of ophthalmology • 2019 • Identification of a Heterozygous Mutation in the TGFBI Gene in a Hui-Chinese Family with Corneal Dystrophy PMID:30915236
• Ophthalmic genetics • 2019 • Granular type I corneal dystrophy in a large consanguineous Tunisian family with homozygous p.R124S mutation in the TGFBI gene PMID:31322463
• Genetic testing • 2008 • p.Ala546 > Asp and p.Arg555 > Trp mutations of TGFBI gene and their clinical manifestations in two large Chinese families with granular corneal dystrophy type I PMID:18752451
• Molecular vision • 2016 • Genetic analysis of CHST6 and TGFBI in Turkish patients with corneal dystrophies: Five novel variations in CHST6 PMID:27829782
• Investigative ophthalmology & visual science • 2003 • Induction of apoptosis in human corneal and HeLa cells by mutated BIGH3 PMID:12824240
• Biochimica et biophysica acta • 2013 • Mutation in transforming growth factor beta induced protein associated with granular corneal dystrophy type 1 reduces the proteolytic susceptibility through local structural stabilization PMID:24129074
• The Journal of biological chemistry • 2011 • Human phenotypically distinct TGFBI corneal dystrophies are linked to the stability of the fourth FAS1 domain of TGFBIp PMID:21135107

Evidence Based Scoring (AI generated)