The TGFBI R555W mutation induces a new granular corneal dystrophy type I phenotype

Abstract

Purpose: To report the clinical and molecular features of a distinct form of transforming growth factor-β-induced (TGFBI) gene-linked corneal dystrophy exhibiting a new granular corneal dystrophy type I (CDGG1) phenotype.

Methods: A complete ophthalmologic examination was performed in all individuals of a Chinese family in which autosomal dominant transmission of the disease had been observed. DNA was obtained from the peripheral blood leukocytes of each participating subject. Genetic analyses included keratin 3 (KRT3), keratin 12 (KRT12), and TGFBI polymerase chain reaction (PCR) amplification and automated nucleotide sequencing of exons from the genomic DNA.

Results: The corneal phenotype in this pedigree was characterized by multiple bilateral dot-like, circular opacities at different corneal depths, with some of the affected individuals only having opacities in the epithelium, which is different from the typical CDGG1 phenotype. TGFBI analysis revealed a heterozygous point mutation at exon 12 (c.1663C>T) in all of the affected individuals, predicting a p.R555W missense mutation.

Conclusions: The phenotype which resulted from the TGFBI R555W mutation in this family is distinct from that observed in the typical case of CDGG1. We propose this disorder should be classified as a new phenotype of CDGG1, and this finding demonstrates the importance of gene diagnosis in the corneal dystrophies.

Figure 1

Pedigree demonstrating the six generations of affected members in a Chinese family having a p.R555W mutation in the TGFBI gene. The filled symbols represent the affected individuals. *=Individuals in whom molecular genetic investigation was performed. The arrow indicates the proband.

Figure 2

Clinical photographs of patients with atypical CDGG1. A: A slit lamp photograph of the proband's cornea (Figure 1, V2) showing multiple round and dot-like grayish white opacities in the central stroma. B: A slit lamp photograph of the proband's cornea showing the opacities in the epithelium and anterior stroma. C: A slit lamp photograph of the cornea in patient IV6 (Figure 1, IV6) showing the opacities in the epithelium and total stroma. D: A slit lamp photograph of the cornea in patient IV20 (Figure 1, IV20) showing opacities only in the epithelium.

Figure 3

Sequence chromatogram from exon 12 of the TGFBI gene showing the region around codon 555 to illustrate a heterozygous C to T transition in the affected individuals. The sense strand is shown; codon 555 is boxed.