A Novel Variant of Granular Corneal Dystrophy Caused by Association of 2 Mutations in the TGFBI Gene—R124L and ΔT125-ΔE126

OBJECTIVE To characterize the molecular defect in the TGFBI gene in a French family affected with an atypical granular corneal dystrophy. PATIENTS This family comprises 9 affected individuals across 3 generations without consanguineous marriage. METHODS Light and electron microscopy were used to examine corneal buttons from patients. Exons of the TGFBI gene were amplified by polymerase chain reaction and sequenced directly using an automated method. Restriction digestion analysis and heteroduplex screening were performed to confirm that the mutations identified were not polymorphisms. RESULTS Round or snow-flakes-like deposits that stained red with Masson trichrome and appeared as dense, rod-shaped structures were observed in the most anterior layers of the central stroma. All patients were heterozygous for the R124L mutation and a novel mutation predicting the deletion of 2 amino acid residues-threonine (T) and glutamic acid (E)-at codons 125 and 126. CONCLUSIONS This French family is affected with a novel variant of granular dystrophy that is caused by a molecular defect in the TGFBI gene, reported here for the first time. CLINICAL RELEVANCE These 2 mutations cause a novel variant of granular dystrophy that is intermediate in severity between the classical and superficial variant forms. Arch Ophthalmol. 2000;118:814-818

[1]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[2]  Y. Tano,et al.  Severe corneal dystrophy phenotype caused by homozygous R124H keratoepithelin mutations. , 1998, Investigative ophthalmology & visual science.

[3]  Tatsuo Yamaguchi,et al.  A new L527R mutation of the βIGH3 gene in patients with lattice corneal dystrophy with deep stromal opacities , 1998, Human Genetics.

[4]  Y. Tano,et al.  Granular corneal dystrophy with homozygous mutations in the kerato-epithelin gene. , 1998, American journal of ophthalmology.

[5]  K. Fujiki,et al.  Homozygotic Patient with βig‐h3 Gene Mutation in Granular Dystrophy , 1998, Cornea.

[6]  Y. Tano,et al.  A kerato-epithelin (betaig-h3) mutation in lattice corneal dystrophy type IIIA. , 1998, American journal of human genetics.

[7]  W. Culbertson,et al.  Mutation hot spots in 5q31-linked corneal dystrophies. , 1998, American journal of human genetics.

[8]  D. Paslier,et al.  Kerato-epithelin mutations in four 5q31-linked corneal dystrophies , 1997, Nature Genetics.

[9]  L. Madisen,et al.  cDNA cloning and sequence analysis of βig-h3, a novel gene induced in a human adenocarcinoma cell line after treatment with transforming growth factor-β , 1992 .

[10]  J. Clarke,et al.  Sequence of DNA flanking the exons of the HEXA gene, and identification of mutations in Tay-Sachs disease. , 1991, American journal of human genetics.

[11]  H. Møller.  Inter‐familial variability and intra‐familial similarities of granular corneal dystrophy Groenouw type I with respect to biomicroscopical appearance and symptomatology , 1989, Acta ophthalmologica.

[12]  Lloyd M. Smith,et al.  Fluorescence detection in automated DNA sequence analysis , 1986, Nature.

[13]  R. Gaster,et al.  Unusual superficial confluent form of granular corneal dystrophy. , 1983, Ophthalmology.

[14]  S. I. Brown,et al.  Granular dystrophy of the cornea. Characteristic electron microscopic lesion. , 1970, Archives of ophthalmology.

[15]  L. Zimmerman,et al.  Histopathologic differentiation of granular, macular and lattice dystrophies of the cornea. , 1961, American journal of ophthalmology.

[16]  N. Shimizu,et al.  A novel mutation at codon 124 (R124L) in the BIGH3 gene is associated with a superficial variant of granular corneal dystrophy. , 1999, Archives of ophthalmology.

[17]  V. Sheffield,et al.  Three autosomal dominant corneal dystrophies map to chromosome 5q , 1994, Nature Genetics.

[18]  M. Javadi,et al.  Superficial juvenile granular dystrophy. , 1992, Ophthalmology.