Abstract
We investigated the clinical and genetic features of patients with severe phenotype of granular corneal dystrophy type 2 (GCD2) associated with compound heterozygosity in the transforming growth factor-β-induced (TGFBI) gene. Patients with severe GCD2 underwent ophthalmic examination (best-corrected visual acuity test, intraocular pressure measurement, slit-lamp examination, and slit-lamp photograph analysis) and direct Sanger sequencing of whole-TGFBI. The patient’s family was tested to determine the pedigrees. Five novel mutations (p.(His174Asp), p.(Ile247Asn), p.(Tyr88Cys), p.(Arg257Pro), and p.(Tyr468*)) and two known mutations (p.(Asn544Ser) and p.(Arg179*)) in TGFBI were identified, along with p.(Arg124His), in the patients. Trans-phase of TGFBI second mutations was confirmed by pedigree analysis. Multiple, extensive discoid granular, and increased linear deposits were observed in the probands carrying p.(Arg124His) and other nonsense mutations. Some patients who had undergone phototherapeutic keratectomy experienced rapid recurrence (p.(Ile247Asn) and p.(Asn544Ser)); however, the cornea was well-maintained in a patient who underwent deep anterior lamellar keratoplasty (p.(Ile247Asn)). Thus, compound heterozygosity of TGFBI is associated with the phenotypic variability of TGFBI corneal dystrophies, suggesting that identifying TGFBI second mutations may be vital in patients with extraordinarily severe phenotypes. Our findings indicate the necessity for a more precise observation of genotype–phenotype correlation and additional care when treating TGFBI corneal dystrophies.
Highlights
We investigated the clinical and genetic features of patients with severe phenotype of granular corneal dystrophy type 2 (GCD2) associated with compound heterozygosity in the transforming growth factor-β-induced (TGFBI) gene
We further performed in vitro experiments to investigate the effect of the identified mutations as well as p.(Arg124His) on transforming growth factor beta-induced protein (TGFBIp) aggregation
The current study demonstrated that simultaneous presence of mutations, such as p.(His174Asp), p.(Ile247Asn), p.(Tyr88Cys), p.(Arg257Pro), p.(Asn544Ser), p.(Arg179*), and p.(Tyr468*), along with p.(Arg124His), in transforming growth factor beta-induced gene (TGFBI) in a compound heterozygous pattern could result in the severe phenotype of GCD2. p.(Tyr88Cys), p.(Arg179*), or p.(Tyr468*) mutation showed increased number or size of granules, while the other mutations showed increased amounts of linear deposits
Summary
We investigated the clinical and genetic features of patients with severe phenotype of granular corneal dystrophy type 2 (GCD2) associated with compound heterozygosity in the transforming growth factor-β-induced (TGFBI) gene. Compound heterozygosity of TGFBI is associated with the phenotypic variability of TGFBI corneal dystrophies, suggesting that identifying TGFBI second mutations may be vital in patients with extraordinarily severe phenotypes. Several transforming growth factor beta-induced gene (TGFBI) mutations, with corneal deposit formation and specific clinical phenotypes, have been reported to date[1,2]. Granular corneal dystrophy type 2 (GCD2) is an autosomal dominant disorder caused by p.(Arg124His) mutation of TGFBI5. The phenotypic variability of heterozygous GCD2 (p.(Arg124His) mutation) in the cornea is considerable, from few subtle white dots to multiple severe opacities throughout the stroma, even at relatively young a ges[9,10]. We further performed in vitro experiments to investigate the effect of the identified mutations as well as p.(Arg124His) on TGFBIp aggregation
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