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A. L. Vincent, B. de Karolyi, D. V. Patel, C. Wheeldon, T. Sherwin, C. N. J. McGhee; A Unique Variant of Corneal Dystrophy of Bowman’s Layer Associated With TGFBI H626P Mutation: A Novel Phenotype-Genotype Correlation. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5859.
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© ARVO (1962-2015); The Authors (2016-present)
Corneal dystrophy of Bowman’s layer (CDB) belongs to a group of corneal dystrophies associated with mutations in the gene Transforming Growth Factor- Beta-Induced (TGFBI). CDB is further divided into a geographic variant, CDBI/Reis-Buckler, and a honeycomb type, CDBII/ Thiel-Benke. We undertook mutational analysis of TGFBI in 3 generation pedigree with an unusual CDB variant and describe a novel phenotype-genotype association.
After informed consent, 15 individuals from a pedigree with an unusual variant of corneal dystrophy of Bowman’s layer were recruited, and underwent extensive phenotyping, includinghistory, visual acuity,slit lamp examination and photography, in vivo confocal microscopy, histological examination of corneal buttons obtained at penetrating keratoplasty from 3 individuals, and electron microscopy of a re-grafted corneal button with disease recurrence. DNA samples were obtained from the individuals. PCR and sequencing of the 17 coding exons of TGFBI was undertaken.Characterisation of the mutant TGFBI protein in the regrafted corneal button with recurrence is currently underway.
A diagnosis was made of atypical CDB with an early onset of severe symptoms and geographic appearance of scarring requiring grafting in late teens consistent with CDBI, but histologically consistent with CDBII. Subepithelial hyaline deposits were negative for Massons trichrome, congo red and alcian blue stains, with focal absence of Bowmans membrane. A TGFBI exon 14 mutation, H626P, segregated with the disease in this pedigree. This mutation was confirmed with NLAIII restriction enzyme digest, and not seen in 100 control chromosomes. The proband's first cousin has posterior polymorphous dystrophy, but does not carry the H626P mutation.
The mutation H626P has previously only been described in a family with an asymmetric late-onset lattice corneal dystrophy. The only TGFBI mutation previously described segregating with CBDI is R124L, while R555Q is described segregating with CBDII. An atypical CBD is described occurring with a 623 mutation. Phenotypic features of the CDB dystrophy in this pedigree are sufficiently atypical to fit either into the CDBI or II classification. The pedigree presented therefore represents a novel phenotype-genotype correlation, and suggests mutations in the 626 region, at the end of the fasc4 domain, show marked phenotypic variability. This contributes to the complexity of pathogenesis of TGFBI-associated corneal dystrophies.
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