A corneal dystrophy associated with transforming growth factor beta-induced Gly623Asp mutation an amyloidogenic phenotype.
OBJECTIVE
To present the light and electron microscopic findings of a unique corneal dystrophy never before described in a German family carrying the Gly623Asp Mutation of the TGFBI gene with late clinical onset.


METHODS
Experimental study.


METHODS
Four affected and 6 nonaffected family members.


METHODS
Slit-lamp examination, photographic documentation, and isolation of genomic DNA from peripheral blood leucocytes obtained from each family member examined. Exons 3, 4, 5, and 11 to 14 of the TGFBI gene were amplified and sequenced in these family members. Five corneal buttons of 3 affected siblings were excised at the time of penetrating keratoplasty. Light and electron microscopic examination were performed including immunohistochemistry with antibodies against keratoepithelin (KE) 2 and 15.


METHODS
Clinical and histologic characteristics of corneal opacification in affected patients and presence of coding region changes in the TGFBI gene.


RESULTS
The specimens showed destructive changes in Bowman's layer and the adjacent stroma. Patchy Congo red-positive amyloid deposits were found within the epithelium in 1 cornea, in Bowman's layer and in the anterior stroma of all specimens also showing KE2, but not KE15, immunostaining. Electron microscopy revealed deposits mainly located in the anterior stroma and Bowman's layer and in small amounts in the basal area of some epithelial cells. The destroyed areas were strongly Alcian blue-positive, the Masson Trichrome stain proved mainly negative for the deposits. All affected but none of the unaffected family members had a heterozygous missense mutation in exon 14 of the TGFBI gene (G-->A transition at nucleotide 1915) replacing glycin by aspartic acid amino acid (Gly623Asp) at position 623 of the KE protein.


CONCLUSIONS
In contrast with the patient carrying the Gly623Asp mutation of the TGFBI gene described by Afshari et al, our cases presented with Salzmann's nodular degeneration-like clinical features and their specimens contained KE2-positive amyloid. The reason for this now "meeting the expectation histologic phenotype" is unclear. The histologic findings emphasize that this is a unique corneal dystrophy, which shares no clinical characteristics with Reis-Bücklers' dystrophy and should be treated as a distinct entity.


BACKGROUND
The authors have no proprietary or commercial interest in any materials discussed in this article.
Auw-Haedrich
Claudia
C
University Eye Hospital, Freiburg, Germany.
Agostini
Hansjürgen
H
Clausen
Ina
I
Reinhard
Thomas
T
Eberwein
Philipp
P
Schorderet
Daniel F
DF
Gruenauer-Kloevekorn
Claudia
C
D000328:Adult; D000368:Aged; D000682:Amyloid / Q000378:metabolism; D028226:Amyloidosis, Familial / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001216:Asparagine / Q000235:genetics; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D005998:Glycine / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics*; D014792:Visual Acuity; D000099222:betaIG-H3 Protein
D000682:Amyloid; D001216:Asparagine; D016326:Extracellular Matrix Proteins; D005998:Glycine; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000099222:betaIG-H3 Protein; C508960:TGFB1 protein, human