TGFBI gene mutations in a Korean population with corneal dystrophy

Abstract

Purpose: To investigate the clinical and genetic features of Korean patients with corneal dystrophies associated with mutations in the human transforming growth factor-β-induced (TGFBI) gene.

Methods: In this study, 387 subjects (71 families and 89 individuals - 268 patients having TGFBI corneal dystrophies and 119 normal relatives) were assessed. All subjects underwent a complete ophthalmologic evaluation, including biomicroscopic inspection and dilated fundus examination. As a control, 100 individuals without corneal disease were selected from the general population. The polymerase chain reaction (PCR) and direct sequencing were used to screen for mutations in TGFBI.

Results: All subjects recruited exhibited a range of corneal dystrophies, including Thiel-Behnke corneal dystrophy (TBCD, R555Q; 6 families and 4 individuals), granular corneal dystrophy type 2 (GCD2, R124H; 61 families and 80 individuals), lattice corneal dystrophy (LCD; 4 families and 5 individuals; 7 with type 1 [R124C], and 2 with a variant [L527R, P542R]). The disease showed an autosomal dominant inheritance pattern in all families.

Conclusions: R124H in GCD2 was the most common mutation. GCD1 and Reis-Bucklers corneal dystrophy were not found. In the GCD2 patients there were a large number of laser refractive surgery-induced corneal opacities. A spontaneous R124H mutation was confirmed in an already mutated allele that resulted in a change from a heterozygous into a homozygous form. Also, a novel mutation, P527R, was identified in LCD.

Figure 1

Phenotypes of Thiel-Behnke corneal dystrophy (all carried the R555Q mutation of the heterozygous form). A: An 11-month-old female, irregularly shaped scattered opacities with non-involvement of the peripheral cornea in the Bowman layer. B: A 26-year-old female, subepithelial reticular (honeycomb) opacities with non-involvement of the peripheral cornea. C: A 43-year-old female, opacities united, resulting in denser and larger opacities. D: A 69-year-old female, opacities, progressing to the deep stromal layers and corneal periphery.

Figure 2

Phenotypes of granular corneal dystrophy, type 2 (all carried the R124H mutation). A: A 16-year-old male, subtle superficial stromal tiny whitish dots. B: A 24-year-old female, rings or stellate-shaped snowflake stromal opacities appeared between the superficial stroma and the mid stroma. C: A 34-year-old male, lattice lines in the deeper cornea (white arrow). D: A 47-year-old female, star-shaped stromal opacities (yellow arrow). E: A 55-year-old male. F: A 65-year-old female, more superficial, translucent, flattened breadcrumb opacities. G: A 77-year-old female, opacities coalesced in the anterior stroma. H: A 39-year-old female with a history of LASIK surgery, diffuse, confluent, white, and small opacities (green arrow) coexisted with discrete and granular opacities (red arrow).

Figure 3

Family with granular corneal dystrophy, Type 2, in which a spontaneous R124H mutation was added to an already mutated allele, resulting in a change from a heterozygous to a homozygous form. A: A 6-year-old female (proband, homozygous form), dense and confluent opacities with peripheral cornea non-involvement in the stromal layer. B: A 32-year-old male (father of proband, heterozygous form), star- and disc- shaped opacities. C: Pedigree, homozygous R124H mutation (CGC→CAC), heterozygous R124H mutation, and no mutations in the proband, father or mother.

Figure 4

Phenotype of variant lattice corneal dystrophy (L527R mutation) with asymmetric corneal opacity in eye laterality, in a 67-year-old female. A, B: Several bifurcating, thick lattice lines in the superficial stroma of the right cornea. C, D: Discrete and nodular opacities were noted in the deep stroma of the central cornea. E: DNA sequence analysis of the TGFBI gene (upper) and a heterozygous point mutation, CTG→CGG (c.1580 T>G: Leu527Arg in exon 12) in codon 527 (bottom).

Figure 5

Family with variant lattice corneal dystrophy (novel mutation R542P). A, B: An 87-year-old female (proband), relatively thick lattice lines (white arrow) that extended from limbus to limbus in the superficial and deep stromal layers. C: A 55-year-old male (daughter of proband), lattice lines discrete in the superficial stroma of the central cornea. D, E: Histopathology (proband, 40× and 100×, respectively), Congo red-positive deposits in almost an entire corneal stroma layer. F: DNA sequence analysis of the TGFBI gene (upper) and a heterozygous point mutation, CCC→CGC (c.1625 C>G: Pro542Arg in exon 12) in codon 542 (bottom). G: Pedigree, heterozygous P542R mutation in the proband and her two daughters.