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Hereditary Lattice Corneal Dystrophy Is Associated with Corneal Amyloid Deposits Enclosing C-Terminal Fragments of Keratoepithelin

¹From the Institute of Pathology and the ⁶Department of Ophthalmology, Otto-von-Guericke University, Magdeburg, Germany; the ²Department of Ophthalmology and the ³Institute of Pathology, Klinikum Kassel, Kassel, Germany; the ⁴Institute of Molecular Biotechnology, Jena, Germany; the ⁵Institut de Recherche en Ophthalmologie, Sion, Switzerland; and the ⁷Department of Computational Biology, International University, Bremen, Germany.

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 TC 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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