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A. Huang, C. Yuan, S.E. Pambuccian; Single Nucleotide Polymorphism in the BIGH3 Gene Promoter in a Case of Presumed Corneal Lattice Dystrophy . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5900.
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We have previously reported that the BIGH3 gene promoter is located within 1 Kb upstream of the start codon. However, mutations of the gene promoter have not been associated with BIGH3–related corneal dystrophies. We investigated the implications of BIGH3 gene promoter mutations in a case of presumed lattice corneal dystrophy.
An 86–year–old Caucasian female was referred for painful pseudophakic corneal edema in the right eye and underwent penetrating keratoplasty for pain control. Slit lamp examinations revealed branching lattice lines in the corneal stroma of the left eye. The host corneal button was examined with Congo red and immunohistochemical studies. Genomic DNA was extracted from host blood for molecular analysis of the BIGH3 gene. All 17 exons and the promoter of BIGH3 gene were PCR–amplified and sequenced for any potential mutations. A constructed luciferase reporter plasmid containing the 1 kb BIGH3 promoter was transfected into A549 cells to investigate transcriptional activities affected by the mutations of BIGH3 gene promoter in vitro.
Branching dendritic lines typical of classic lattice corneal dystrophy were noted in both eyes. Sections of the corneal button were positive with Congo red staining in the mid– to deep stroma, indicating the presence of amyloid deposits. In addition, these amyloid deposits were also positive by our custom–made anti–BIGH3 antibody. However, no missense mutations were found in all 17 exons of BIGH3 gene from the proband’s genomic DNA. Of significance, a novel single nucleotide polymorphism (SNP, A–to–G mutation) in the promoter region located at the –870 bp upstream of the ATG start codon was identified. Using luciferase reporter, promoter containing this SNP displayed a significantly higher transcriptional activity, independent of TGFß–1 treatment.
A SNP in the BIGH3 gene promoter region without any other mutation in the coding region was identified in a case of presumed lattice corneal dystrophy displaying classic amyloid deposits in corneal stroma. The SNP of the gene promoter appears to up–regulate the BIGH3 gene transcription.
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