title: Polymorphic corneal amyloidosis: a disorder due to a novel mutation in the transforming growth factor beta-induced (BIGH3) gene.
abstract: OBJECTIVE
  To characterize the clinicopathologic phenotype as well as the molecular genetic basis of an autosomal dominant form of corneal amyloidosis.
  
  
  METHODS
  Clinicopathologic and molecular genetic study of a family with a form of corneal amyloidosis.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Eifrig
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Afshari
authors.forename: Harry W
authors.initials: HW
authors.lastname: Buchanan
authors.forename: Brandy L
authors.initials: BL
authors.lastname: Bowling
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Klintworth
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000686:Amyloidosis / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D002648:Child; D003316:Corneal Diseases / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D003318:Corneal Opacity / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D015948:Keratoplasty, Penetrating; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012086:Reoperation; D016212:Transforming Growth Factor beta / Q000235:genetics*; D000099222:betaIG-H3 Protein
chemical_list: D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein