Heterogeneity in granular corneal dystrophy: identification of three causative mutations in the TGFBI (BIGH3) gene-lessons for corneal amyloidogenesis

Hum Mutat. 1999;14(2):126-32. doi: 10.1002/(SICI)1098-1004(1999)14:2<126::AID-HUMU4>3.0.CO;2-W.


Six autosomal dominant corneal dystrophies are caused by mutations in the TGFBI (BIGH3) gene on chromosome 5q31: three types of lattice corneal dystrophy (LCD), including type I and type IIIA, granular, Avellino (ACD), and Reis-Bucklers. Initially an exact genotype-phenotype correlation was reported. We report three families, with differing clinical features, all presenting with "granular" corneal dystrophy. We analysed the TGFBI gene by SSCP analysis and direct sequencing in order to further assess the genotype-phenotype correlation. We describe three separate mutations in TGFBI: one novel, one initially described as causing ACD, and one previously described. The novel mutation, R124S, is at the identical position to the mutation causing LCD type I (CDL1). We review the clinical and histological phenotypes of the corneal dystrophies and hypothesize that the ability of a mutation to cause amyloid deposition depends on the location and nature of the mutation. In addition, we suggest that the classification of the granular corneal dystrophies be revised according to mutation type and that ACD should not be classified as a distinct morphological entity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / metabolism
  • Chromosomes, Human, Pair 5 / genetics
  • Cornea / metabolism
  • Cornea / pathology
  • Corneal Dystrophies, Hereditary / classification
  • Corneal Dystrophies, Hereditary / genetics*
  • DNA Mutational Analysis
  • Female
  • Genotype
  • Histocytochemistry
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Phenotype
  • Polymorphism, Single-Stranded Conformational
  • Transforming Growth Factor beta / genetics*


  • Amyloid
  • Transforming Growth Factor beta