Purpose To evaluate the TGFBI gene and the encoded transforming growth factor beta-induced protein (TGFBIp) in a 47-year-old African-American patient with an unusual atypical asymmetric lattice corneal dystrophy (LCD). Methods The eyes of the proband and his brother were examined by slit-lamp biomicroscopy and their clinical records were reviewed. All 17 exons of TGFBI were evaluated in genomic DNA extracted from blood or buccal epithelial cell samples from the proband and his family members. The corneal tissue of the proband was examined histopathologically, and TGFBIp was analyzed in half of an excised corneal button. Results The proband (who had an unusual atypical asymmetric LCD) and his brother (who had mild bilateral deep stromal opacities) were found to have homozygous Val624Met mutations in TFGBI. The proband’s daughter who was heterozygous for the Val624Met mutation had no reported ophthalmic abnormalities. The corneal tissue from the proband contained TGFBIp with the Val624Met mutation. Patients with LCD have different clinical phenotypes based on their genotype. Molecular genetic analyses are becoming increasingly important in making precise diagnoses and prognostic predictions about inherited corneal disorders. Conclusions A novel Val624Met homozygous mutation in TGFBI was associated with atypical LCD in two family members. Symptomatic corneal disease was absent at the age of 24 years in the offspring of the proband who was heterozygous for this mutation. This is an apparent example of a TGFBI mutation that becomes evident when it is homozygous. The finding of Val624Met mutated TGFBIp in a ~65 kDa protein band in a reduced sodium dodecyl sulfate (SDS) gel suggests that the accumulated protein was intact TGFBIp and not a fragment of TGFBIp.

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Purpose: To characterize the clinicopathologic phenotype as well as the molecular genetic basis of an autosomal dominant form of corneal amyloidosis.Design: Clinicopathologic and molecular genetic study of a family with a form of corneal amyloidosis.Participants: Forty-nine individuals from one family were studied.Methods: The medical records of affected family members were reviewed, and corneal tissue from those who had undergone penetrating keratoplasty (PK) was examined. Several family members were examined clinically, and corneas were photographed. Deoxyribonucleic acid from blood or buccal swabs was extracted from each consenting family member to determine the status of their transforming growth factor beta-induced (TGFBI) gene. The coding region of the TGFBI gene was analyzed for mutations in the proband's DNA, and compared with the nucleotide sequences of normal individuals. This was performed by amplifying and sequencing all exons of the TGFBI gene. In all other family members, only exons 4, 8, 11, and 12 of the gene were amplified, sequenced, and analyzed for mutations.Main Outcome Measures: Clinicopathologic manifestations in relation to mutational status of the TGFBI gene.Results: Slit-lamp biomicroscopy revealed bilateral multiple polymorphic, polygonal, refractile, chipped ice-appearing gray and white opacities. There were also occasional deep filamentous lines that did not form a distinct lattice pattern. Corneal tissue of affected individuals who underwent PK contained widespread deposits of amyloid within the corneal stroma, particularly in the deep central stroma. Twelve members of the family were found to have a heterozygous single mutation in the TGFBI gene leading to a predicted amino acid substitution of aspartic acid for alanine (A546D). Nine of these individuals had ophthalmologist-documented corneal disease. The remaining 3, who were 11, 14, and 15 years old, were asymptomatic. In addition, 4 inconsequential polymorphisms with the nucleotide changes 387 G/A (R129R), 981 G/A (V327V), 1416 T/C (L472L), and 1620 C/T (F540F) were found.Conclusion: A distinct, progressive form of corneal amyloidosis with an autosomal dominant mode of inheritance is characterized clinically by the presence of refractile polymorphic corneal opacities. We have designated this entity, which is caused by an A546D mutation in the TGFBI gene, polymorphic corneal amyloidosis. (C) 2004 by the American Academy of Ophthalmology.