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Barbara Stix, Martina Leber, Peter Bingemer, Christof Gross, Josef Rüschoff, Marcus Fändrich, Daniel F. Schorderet, Christian K. Vorwerk, Martin Zacharias, Albert Roessner, Christoph Röcken; Hereditary Lattice Corneal Dystrophy Is Associated with Corneal Amyloid Deposits Enclosing C-Terminal Fragments of Keratoepithelin. Invest. Ophthalmol. Vis. Sci. 2005;46(4):1133-1139. doi: 10.1167/iovs.04-1319.
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purpose. To investigate the molecular basis of hereditary lattice corneal dystrophy (LCD) type IIIA associated with corneal amyloid deposits afflicting several members of a four-generation family.
methods. Histologic, immunohistochemical and biochemical studies were performed on corneal tissue samples obtained after perforating keratoplasty. DNA was extracted from peripheral blood leukocytes. All exons of the keratoepithelin-encoding TGFBI gene were amplified and sequenced. The presence of a mutation was confirmed by digestion of the isolated PCR product with the restriction enzyme AlwNI.
results. The cornea of the index patient (II-1) contained large patchy deposits of amyloid, which were immunoreactive for the C terminus of keratoepithelin. Western blot analysis of the polypeptide chains extracted from the amyloid deposits of paraffin-embedded tissue revealed that these represented mainly fragments of the full-length protein. The smallest fragments were 6.5 and 6.9 kDa. DNA analyses of the TGFBI gene revealed a heterozygous T→C transition at the second position of codon 540 in exon 12, indicating that replacement of phenylalanine by serine (Phe540Ser) leads to dominant disease. The mutation creates a new restriction site for the enzyme AlwNI. Five of the examined family members carried this mutation. Three of them (aged ≥41 years) had the disease, two family members (aged <20 years) do not yet show any clinical symptoms. An additional inconsequential single-nucleotide polymorphism (T1667C) was found at the third position of the same codon (Phe540Phe) in three unaffected family members.
conclusions. This is the first report of a single-nucleotide mutation at codon 540 of TGFBI leading to LCD, and the first to demonstrate that the amyloid deposits in LCD contain proteolytic fragments of keratoepithelin.
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