Polymorphic corneal amyloidosis: A disorder due to a novel mutation in the Transforming Growth Factor β–Induced (BIGH3) gene☆
Presented in part at: Association for Research in Vision and Ophthalmology Annual Meeting, May 7, 2003; Ft. Lauderdale, Florida.
Received 20 June 2003; accepted 15 September 2003.
Abstract
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 β–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.
1Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, USA
2Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA
3Department of Surgery, Division of Ophthalmology, Sacred Heart Hospital, Allentown, Pennsylvania, USA
Reprint requests to Gordon K. Klintworth, MD, PhD, 255 Medical Sciences Research Building, Box 3802 Duke University Medical Center, Durham, NC 27710, USA.
Research funding was provided by a research grant from the National Eye Institute, Bethesda, Maryland (grant no.: R01EY2712). Dr Afshari has a research career development award from Research to Prevent Blindness, New York, New York.
ABSTRACT