title: Spontaneous and inheritable R555Q mutation in the TGFBI/BIGH3 gene in two unrelated families exhibiting Bowman's layer corneal dystrophy.
abstract: OBJECTIVE
  Bowman's layer corneal dystrophies (CDBs) include 2 distinct types: CDB1, or Reis-Bücklers (RBCD), and CDB2, or Thiel-Behnke (TBCD). We studied the genetic basis of 2 cases of apparent spontaneous CDB mutations and attempted to determine if these are sporadic and inheritable mutations.
  
  
  METHODS
  Retrospective molecular genetic study and case report.
  
  
  METHODS
  Twelve patients were recruited from 2 unrelated families for this study, including 2 affected individuals from one family (family A) and 1 affected individual from another (family B).
  
  
  METHODS
  Slit-lamp examination was performed for each patient to determine the disease phenotype. Histological analysis of affected cornea specimens was used for identification of pathogenic corneal opacities in 2 affected patients from family A.
  
  
  METHODS
  Genomic DNA was isolated from the blood samples and used for mutation screening of the TGFBI/BIGH3 gene. Sixteen polymorphic DNA markers from 9 different chromosomes were used to establish the maternity and paternity of the 2 probands.
  
  
  RESULTS
  The 2 families were confirmed to be unrelated. The age onset of ocular symptoms was <2 years for all 3 affected patients. Clinical diagnoses of CDB1 (RBCD) and CDB2 (TBCD) were made for probands A and B, respectively. The affected corneas showed epithelial haze with diffuse, irregular, patchy opacities in a honeycomb and geographic pattern. Subepithelial plaques, increased trichome staining of anterior stroma, and irregular Bowman's layer were observed. An R555Q mutation was found in TGFBI/BIGH3 in the 2 probands but not in their parents. The son of proband A was also affected and apparently inherited his disease allele from his father.
  
  
  CONCLUSIONS
  The R555Q mutation occurred spontaneously and independently in the 2 unrelated CDB families and was confirmed to be transmitted to the next generation in 1 of the 2 families. These findings strongly support the notion that a genetic diagnosis should be determined for CDB and other dystrophies associated with mutations in TGFBI/BIGH3. The discovery of a spontaneous mutation should alert clinicians to be aware of the existence of genetic alterations for their patients without apparent family history of the disease.
authors.affiliation: Department of Ophthalmology and Visual Science and Hermann Eye Center, University of Texas Health Science Center at Houston, Houston, Texas, USA. Xinping.Zhao@uth.tmc.edu
authors.forename: Xinping C
authors.initials: XC
authors.lastname: Zhao
authors.forename: Hisashi
authors.initials: H
authors.lastname: Nakamura
authors.forename: Sumitra
authors.initials: S
authors.lastname: Subramanyam
authors.forename: Lee E
authors.initials: LE
authors.lastname: Stock
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Gillette
authors.forename: Shunichi
authors.initials: S
authors.lastname: Yoshikawa
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Ma
authors.forename: Richard W
authors.initials: RW
authors.lastname: Yee
mesh_terms: D017668:Age of Onset; D050541:Bowman Membrane / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics* / Q000601:surgery; D016039:Corneal Transplantation; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; 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